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Ranjbarnejad T, Abolhassani H, Sherkat R, Salehi M, Ranjbarnejad F, Vatandoost N, Sharifi M. Exploring Monogenic, Polygenic, and Epigenetic Models of Common Variable Immunodeficiency. Hum Mutat 2025; 2025:1725906. [PMID: 40265101 PMCID: PMC12014265 DOI: 10.1155/humu/1725906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 12/21/2024] [Accepted: 03/21/2025] [Indexed: 04/24/2025]
Abstract
Common variable immunodeficiency (CVID) is the most frequent symptomatic inborn error of immunity (IEI). CVID is genetically heterogeneous and occurs in sporadic or familial forms with different inheritance patterns. Monogenic mutations have been found in a low percentage of patients, and multifactorial or polygenic inheritance may be involved in unsolved patients. In the complex disease model, the epistatic effect of multiple variants in several genes and environmental factors such as infections may contribute. Epigenetic modifications, such as DNA methylation changes, are also proposed to be involved in CVID pathogenesis. In general, the pathogenic mechanism and molecular basis of CVID disease are still unknown, and identifying patterns of association across the genome in polygenic models and epigenetic modification profiles in CVID requires more studies. Here, we describe the current knowledge of the molecular genetic basis of CVID from monogenic, polygenic, and epigenetic aspects.
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Affiliation(s)
- Tayebeh Ranjbarnejad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hassan Abolhassani
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Roya Sherkat
- Immunodeficiency Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mansoor Salehi
- Cellular, Molecular and Genetics Research Center, Isfahan University of Medical Science, Isfahan, Iran
| | - Fatemeh Ranjbarnejad
- Medical Biology Research Center, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nasimeh Vatandoost
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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2
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Huang L, Simonian R, Lopez MA, Karuppasamy M, Sanders VM, English KG, Fabian L, Alexander MS, Dowling JJ. X-linked myopathy with excessive autophagy: characterization and therapy testing in a zebrafish model. EMBO Mol Med 2025; 17:823-840. [PMID: 39994482 PMCID: PMC11982336 DOI: 10.1038/s44321-025-00204-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/03/2025] [Accepted: 02/10/2025] [Indexed: 02/26/2025] Open
Abstract
X-linked myopathy with excessive autophagy (XMEA), a rare childhood-onset autophagic vacuolar myopathy caused by mutations in VMA21, is characterized by proximal muscle weakness and progressive vacuolation. VMA21 encodes a protein chaperone of the vacuolar hydrogen ion ATPase, the loss of which leads to lysosomal neutralization and impaired function. At present, there is an incomplete understanding of XMEA, its mechanisms, consequences on other systems, and therapeutic strategies. A significant barrier to advancing knowledge and treatments is the lack of XMEA animal models. Therefore, we used CRISPR-Cas9 editing to engineer a loss-of-function mutation in zebrafish vma21. The vma21 mutant zebrafish phenocopy the human disease with impaired motor function and survival, liver dysfunction, and dysregulated autophagy indicated by lysosomal de-acidification, the presence of characteristic autophagic vacuoles in muscle fibers, altered autophagic flux, and reduced lysosomal marker staining. As proof-of-concept, we found that two drugs, edaravone and LY294002, improve swim behavior and survival. In total, we generated and characterized a novel preclinical zebrafish XMEA model and demonstrated its suitability for studying disease pathomechanisms and identifying potential therapeutic targets.
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Affiliation(s)
- Lily Huang
- Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, M5G 1E8, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 3K3, Canada
| | - Rebecca Simonian
- Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, M5G 1E8, Canada
| | - Michael A Lopez
- Department of Pediatrics, Division of Neurology at the University of Alabama at Birmingham and Children's of Alabama, Birmingham, AL, 35294, USA
- Department of Genetics at the University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Muthukumar Karuppasamy
- Department of Pediatrics, Division of Neurology at the University of Alabama at Birmingham and Children's of Alabama, Birmingham, AL, 35294, USA
- Department of Genetics at the University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Veronica M Sanders
- Department of Pediatrics, Division of Neurology at the University of Alabama at Birmingham and Children's of Alabama, Birmingham, AL, 35294, USA
| | - Katherine G English
- Department of Pediatrics, Division of Neurology at the University of Alabama at Birmingham and Children's of Alabama, Birmingham, AL, 35294, USA
| | - Lacramioara Fabian
- Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, M5G 1E8, Canada
| | - Matthew S Alexander
- Department of Pediatrics, Division of Neurology at the University of Alabama at Birmingham and Children's of Alabama, Birmingham, AL, 35294, USA.
- Department of Genetics at the University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
| | - James J Dowling
- Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, M5G 1E8, Canada.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 3K3, Canada.
- Division of Neurology, Hospital for Sick Children, Toronto, ON, M5G 1E8, Canada.
- Department of Paediatrics, University of Toronto, Toronto, ON, M5G 1E8, Canada.
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Yan Z, Huang A, Ma D, Hong C, Zhang S, He L, Rao H, Luo S. ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy. Cell Death Dis 2025; 16:201. [PMID: 40133274 PMCID: PMC11937278 DOI: 10.1038/s41419-025-07534-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 03/01/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025]
Abstract
Autophagy is a highly conserved cellular process essential for maintaining cellular homeostasis and influencing cancer development. Lysosomal acidification and autophagosome-lysosome fusion are two important steps of autophagy degradation that are tightly regulated. Although many key proteins that regulate these two events have been identified, the effector proteins that co-regulate both steps remain to be explored. ATP6AP1, an accessory subunit of V-ATPase, plays a critical role in the assembly and regulation of V-ATPase. However, the function of ATP6AP1 in autophagy remains unknown, and the role of ATP6AP1 in cancer is still poorly understood. In this study, we found that ATP6AP1 is overexpressed in luminal breast cancer tissues and promotes the proliferation and tamoxifen resistance of luminal breast cancer cells both in vitro and in vivo. We also observed that high ATP6AP1 expression correlates with poor overall patient survival. Our research further revealed that ATP6AP1 enhances tamoxifen resistance by activating autophagy. Mechanistically, ATP6AP1 promotes autophagy by regulating both lysosomal acidification and autophagosome-lysosome fusion. Remarkably, ATP6AP1 induces lysosomal acidification through the regulation of V-ATPase assembly and facilitates autophagosome-lysosome fusion by enhancing the interaction between Rab7 and the HOPS complex. Together, our studies identify ATP6AP1 as a crucial regulator of autophagy, potentially serving as a valuable prognostic marker or therapeutic target in human luminal breast cancer.
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Affiliation(s)
- Zhengwei Yan
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Biochemistry, School of Medicine, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Aidi Huang
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Dongwen Ma
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Chenao Hong
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Shengmiao Zhang
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Luling He
- Department of Biochemistry, School of Medicine, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Hai Rao
- Department of Biochemistry, School of Medicine, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China.
| | - Shiwen Luo
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
- Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
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Cocchiararo I, Castets P. Recent advances in the clinical spectrum and pathomechanisms associated with X-linked myopathy with excessive autophagy and other VMA21-related disorders. J Neuromuscul Dis 2025:22143602251314767. [PMID: 40033998 DOI: 10.1177/22143602251314767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
X-linked myopathy with excessive autophagy (XMEA) is a rare neuromuscular disorder caused by mutations in the VMA21 gene, encoding a chaperone protein present in the endoplasmic reticulum (ER). In yeast and human, VMA21 has been shown to chaperone the assembly of the vacuolar (v)-ATPase proton pump required for the acidification of lysosomes and other organelles. In line with this, VMA21 deficiency in XMEA impairs autophagic degradation steps, which would be key in XMEA pathogenesis. Recent years have witnessed a surge of interest in VMA21, with the identification of novel mutations causing a congenital disorder of glycosylation (CDG) with liver affection, and its potent implication in cancer predisposition. With this, VMA21 deficiency has been further linked to defective glycosylation, lipid metabolism dysregulation and ER stress. Moreover, the identification of two VMA21 isoforms, namely VMA21-101 and VMA21-120, has opened novel avenues regarding the pathomechanisms leading to XMEA and VMA21-CDG. In this review, we discuss recent advances on the clinical spectrum associated with VMA21 deficiency and on the pathophysiological roles of VMA21.
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Affiliation(s)
- Ilaria Cocchiararo
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Perrine Castets
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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5
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Bonacina F, Zhang X, Manel N, Yvan-Charvet L, Razani B, Norata GD. Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis. Nat Rev Cardiol 2025; 22:149-164. [PMID: 39304748 PMCID: PMC11835540 DOI: 10.1038/s41569-024-01072-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/08/2024] [Indexed: 09/22/2024]
Abstract
Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB. By coupling nutrients to downstream signalling and metabolism, lysosomes serve as a crucial hub for cellular function in innate and adaptive immune cells. Lysosomal dysfunction is now recognized to be a hallmark of atherogenesis. Perturbations in nutrient-sensing and signalling have profound effects on the capacity of immune cells to handle cholesterol, perform phagocytosis and efferocytosis, and limit the activation of the inflammasome and other inflammatory pathways. Strategies to improve lysosomal function hold promise as novel modulators of the immunoinflammatory response associated with atherosclerosis. In this Review, we describe the crosstalk between lysosomal biology and immune cell function and polarization, with a particular focus on cellular immunometabolic reprogramming in the context of atherosclerosis.
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Affiliation(s)
- Fabrizia Bonacina
- Department of Excellence of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy
| | - Xiangyu Zhang
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA
- Pittsburgh VA Medical Center, Pittsburgh, PA, USA
| | - Nicolas Manel
- Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, Paris, France
| | - Laurent Yvan-Charvet
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Fédération Hospitalo-Universitaire (FHU), Oncoage, Nice, France
| | - Babak Razani
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA
- Pittsburgh VA Medical Center, Pittsburgh, PA, USA
| | - Giuseppe D Norata
- Department of Excellence of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy.
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6
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García-Cazorla Á, Morava E, Saudubray JM. "Trafficking Disorders: Phenotypical Similarities and Differences With Other IMDs". J Inherit Metab Dis 2025; 48:e70004. [PMID: 39985262 DOI: 10.1002/jimd.70004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 01/19/2025] [Accepted: 01/20/2025] [Indexed: 02/24/2025]
Abstract
Cell trafficking disorders (CTD) are genetic defects in complex molecules and correspond to the largest category of IEM with mutations in more than 370 genes described. They are still poorly recognized as a global entity but rather seen as isolated rare diseases by non-metabolic specialists. Complex lipid metabolism (mostly phospholipids, sphingolipids, and non-mitochondrial fatty acids) is tightly associated with cell trafficking and interactions between organelles at the membrane contact sites. Accordingly, from a clinical point of view CTD presents with multisystem manifestations that may overlap and mimic mitochondrial and other complex molecule disorders such as peroxisomal, lysosomal defects, CDG, or autophagy disorders. The nervous system is especially vulnerable and neurological presentations are prominent, but CTD targets any organ at any age. Interestingly the involvement of the immune system is particularly characteristic of CTD and rarely (or at least little described so far) in other categories of IEM. Most CTD are progressive disorders, except for CDG. They may have "metabolic crises" mimicking disorders of intermediary and energy metabolism for which emergency protocols have been developed. They are generally diagnosed by exome sequencing. Relatively few biomarkers are available.
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Affiliation(s)
- Ángeles García-Cazorla
- Neurometabolic Unit and Synaptic Metabolism Laboratory. Department of Neurology, Hospital Sant Joan de Déu, IRSJD, CIBERER and MetabERN, Barcelona, Spain
| | - Eva Morava
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Jean-Marie Saudubray
- Groupe de Recherche Clinique Neurométabolique, Université Pierre et Marie Curie, Paris, France
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Knight K, Park JB, Oot RA, Khan MM, Roh SH, Wilkens S. Monoclonal nanobodies alter the activity and assembly of the yeast vacuolar H +-ATPase. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.10.632502. [PMID: 39829782 PMCID: PMC11741422 DOI: 10.1101/2025.01.10.632502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
The vacuolar ATPase (V-ATPase; V1Vo) is a multi-subunit rotary nanomotor proton pump that acidifies organelles in virtually all eukaryotic cells, and extracellular spaces in some specialized tissues of higher organisms. Evidence suggests that metastatic breast cancers mislocalize V-ATPase to the plasma membrane to promote cell survival and facilitate metastasis, making the V-ATPase a potential drug target. We have generated a library of camelid single-domain antibodies (Nanobodies; Nbs) against lipid-nanodisc reconstituted yeast V-ATPase Vo proton channel subcomplex. Here, we present an in-depth characterization of three anti-Vo Nbs using biochemical and biophysical in vitro experiments. We find that the Nbs bind Vo with high affinity, with one Nb inhibiting holoenzyme activity and another one preventing enzyme assembly. Using cryoEM, we find that two of the Nbs bind the c subunit ring of the Vo on the lumen side of the complex. Additionally, we show that one of the Nbs raised against yeast Vo can pull down human V-ATPase (HsV1Vo). Our research demonstrates Nb versatility to target and modulate the activity of the V-ATPase, and highlights the potential for future therapeutic Nb development.
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Affiliation(s)
- Kassidy Knight
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Jun Bae Park
- Department of Biological Sciences, Seoul National University, Seoul, Korea
- Present address: Department of Cancer Biology, Lerner research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Rebecca A. Oot
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Md. Murad Khan
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Present address: Howard Hughes Medical Institute, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Soung-Hun Roh
- Department of Biological Sciences, Seoul National University, Seoul, Korea
| | - Stephan Wilkens
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
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Fei Y, Yan X, Liang M, Zhou S, Xu D, Li L, Xu W, Song Y, Zhu Z, Zhang J. Lysosomal gene ATP6AP1 promotes doxorubicin resistance via up-regulating autophagic flux in breast cancer. Cancer Cell Int 2024; 24:394. [PMID: 39627767 PMCID: PMC11616228 DOI: 10.1186/s12935-024-03579-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 11/19/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Breast cancer remains the most prevalent malignancy in women. Chemotherapy is the primary systemic treatment modality, and the effectiveness of treatment is often hampered by chemoresistance. Autophagy has been implicated in promoting chemoresistance, as elevated autophagic flux supports tumor cell survival under therapeutic stress. Since lysosomes are essential for the completion of autophagy, their role in autophagy-related chemoresistance has been insufficiently studied. This study aims to elucidate the role of the lysosomal gene ATP6AP1 in promoting chemoresistance in breast cancer by upregulating autophagic flux. METHODS Doxorubicin-induced cell death was assessed by cytotoxicity, flow cytometry, lactate dehydrogenase (LDH) release assays in various breast cancer cell lines. Autophagic flux was assessed with western blot and the mRFP-GFP-LC3 fluorescence imaging. Breast cancer cells were infected with shRNA lentivirus targeting ATP6AP1, allowing investigation its tole in doxorubicin-induced cell death. ATP6AP1 expression and its association with prognosis were evaluated using public databases and immunohistochemistry. RESULTS Doxorubicin-induced cell death in breast cancer cells is negatively correlated with increased autophagic flux and lysosomal acidification. The lysosomal gene ATP6AP1, which plays a role in autophagic processes, is upregulated in breast cancer tissues. Knocking down ATP6AP1 reduces autophagy-mediated doxorubicin resistance by inhibiting autophagic flux and lysosomal acidification in breast cancer cells. Data analysis from public databases and our cohort indicate that elevated ATP6AP1 expression correlates with poor response to doxorubicin-based neoadjuvant chemotherapy (NAC) and worse prognosis. CONCLUSIONS Doxorubicin-induced cytotoxicity is associated with autophagy flux in breast cancer. The lysosomal gene ATP6AP1 facilitates autolysosome acidification and contributes to doxorubicin resistance in breast cancer.
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Affiliation(s)
- Yinjiao Fei
- Department of Radiation Therapy, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Xueqin Yan
- Department of General Surgery, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Mingxing Liang
- Department of Thyroid Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, 88Jiefang Road, Hangzhou, 310009, People's Republic of China
| | - Shu Zhou
- Department of Radiation Therapy, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Di Xu
- Department of General Surgery, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Lei Li
- Department of General Surgery, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Weilin Xu
- Department of Radiation Therapy, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Yuxin Song
- Department of General Surgery, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Zhen Zhu
- Department of General Surgery, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.
| | - Jian Zhang
- Department of General Surgery, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.
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Lei Y, Yang Y, Zhang Z, Zhang R, Song X, Malek SN, Tang D, Klionsky DJ. Big1 is a newly identified autophagy regulator that is critical for a fully functional V-ATPase. Mol Biol Cell 2024; 35:br20. [PMID: 39259764 PMCID: PMC11617096 DOI: 10.1091/mbc.e24-04-0189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 09/13/2024] Open
Abstract
The vacuolar-type H+-translocating ATPase (V-ATPase) is the major proton pump for intraorganellar acidification. Therefore, the integrity of the V-ATPase is closely associated with cellular homeostasis, and mutations in genes encoding V-ATPase components and assembly factors have been reported in certain types of diseases. For instance, the recurrent mutations of ATP6AP1, a gene encoding a V-ATPase accessory protein, have been associated with cancers and immunodeficiency. With the aim of studying V-ATPase-related mutations using the yeast model system, we report that Big1 is another homologue of ATP6AP1 in yeast cells, and we characterize the role of Big1 in maintaining a fully functional V-ATPase. In addition to its role in acidifying the vacuole or lysosome, our data support the concept that the V-ATPase may function as part of a signaling pathway to regulate macroautophagy/autophagy through a mechanism that is independent from Tor/MTOR.
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Affiliation(s)
- Yuchen Lei
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2216
| | - Ying Yang
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2216
| | - Zhihai Zhang
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2216
| | - Ruoxi Zhang
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Xinxin Song
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Sami N. Malek
- Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109-0936
| | - Daolin Tang
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Daniel J. Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2216
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10
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Patterson AR, Needle GA, Sugiura A, Jennings EQ, Chi C, Steiner KK, Fisher EL, Robertson GL, Bodnya C, Markle JG, Sheldon RD, Jones RG, Gama V, Rathmell JC. Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities. Sci Immunol 2024; 9:eadh0368. [PMID: 39151020 PMCID: PMC11590014 DOI: 10.1126/sciimmunol.adh0368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 07/25/2024] [Indexed: 08/18/2024]
Abstract
Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme Gfpt1 are critical for T cell expansion and function. Further, T helper (TH1) cells synthesized uridine diphosphate N-acetylglucosamine more rapidly and were more impaired by Gfpt1 deficiency than TH17 cells. Screening IEI genes found that Bcl11b promotes the CD4 T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.
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Affiliation(s)
- Andrew R. Patterson
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Gabriel A. Needle
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ayaka Sugiura
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Erin Q. Jennings
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Channing Chi
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - KayLee K. Steiner
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Emilie L. Fisher
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Caroline Bodnya
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Janet G. Markle
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ryan D. Sheldon
- Mass Spectrometry Core, Core Technologies and Services, Van Andel Institute, Grand Rapids, MI, USA
| | - Russell G. Jones
- Department of Metabolism and Nutritional Programming, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Vivian Gama
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Jeffrey C. Rathmell
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
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11
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Oot RA, Wilkens S. Human V-ATPase function is positively and negatively regulated by TLDc proteins. Structure 2024; 32:989-1000.e6. [PMID: 38593795 PMCID: PMC11246223 DOI: 10.1016/j.str.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 02/23/2024] [Accepted: 03/13/2024] [Indexed: 04/11/2024]
Abstract
Proteins that contain a highly conserved TLDc domain (Tre2/Bub2/Cdc16 LysM domain catalytic) offer protection against oxidative stress and are widely implicated in neurological health and disease. How this family of proteins exerts their function, however, is poorly understood. We have recently found that the yeast TLDc protein, Oxr1p, inhibits the proton pumping vacuolar ATPase (V-ATPase) by inducing disassembly of the pump. While loss of TLDc protein function in mammals shares disease phenotypes with V-ATPase defects, whether TLDc proteins impact human V-ATPase activity directly is unclear. Here we examine the effects of five human TLDc proteins, TLDC2, NCOA7, OXR1, TBC1D24, and mEAK7 on the activity of the human V-ATPase. We find that while TLDC2, TBC1D24, and the TLDc domains of OXR1 and NCOA7 inhibit V-ATPase by inducing enzyme disassembly, mEAK7 activates the pump. The data thus shed new light both on mammalian TLDc protein function and V-ATPase regulation.
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Affiliation(s)
- Rebecca A Oot
- Department of Biochemistry & Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
| | - Stephan Wilkens
- Department of Biochemistry & Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
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12
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Eaton AF, Danielson EC, Capen D, Merkulova M, Brown D. Dmxl1 Is an Essential Mammalian Gene that Is Required for V-ATPase Assembly and Function In Vivo. FUNCTION 2024; 5:zqae025. [PMID: 38984989 PMCID: PMC11237898 DOI: 10.1093/function/zqae025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 07/11/2024] Open
Abstract
The proton pumping V-ATPase drives essential biological processes, such as acidification of intracellular organelles. Critically, the V-ATPase domains, V1 and VO, must assemble to produce a functional holoenzyme. V-ATPase dysfunction results in cancer, neurodegeneration, and diabetes, as well as systemic acidosis caused by reduced activity of proton-secreting kidney intercalated cells (ICs). However, little is known about the molecular regulation of V-ATPase in mammals. We identified a novel interactor of the mammalian V-ATPase, Drosophila melanogaster X chromosomal gene-like 1 (Dmxl1), aka Rabconnectin-3A. The yeast homologue of Dmxl1, Rav1p, is part of a complex that catalyzes the reversible assembly of the domains. We, therefore,hypothesized that Dmxl1 is a mammalian V-ATPase assembly factor. Here, we generated kidney IC-specific Dmxl1 knockout (KO) mice, which had high urine pH, like B1 V-ATPase KO mice, suggesting impaired V-ATPase function. Western blotting showed decreased B1 expression and B1 (V1) and a4 (VO) subunits were more intracellular and less colocalized in Dmxl1 KO ICs. In parallel, subcellular fractionation revealed less V1 associated B1 in the membrane fraction of KO cells relative to the cytosol. Furthermore, a proximity ligation assay performed using probes against B1 and a4 V-ATPase subunits also revealed decreased association. We propose that loss of Dmxl1 reduces V-ATPase holoenzyme assembly, thereby inhibiting proton pumping function. Dmxl1 may recruit the V1 domain to the membrane and facilitate assembly with the VO domain and in its absence V1 may be targeted for degradation. We conclude that Dmxl1 is a bona fide mammalian V-ATPase assembly factor.
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Affiliation(s)
- Amity F Eaton
- Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Elizabeth C Danielson
- Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Diane Capen
- Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Maria Merkulova
- Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Dennis Brown
- Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
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13
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Morales-Romero B, Muñoz-Pujol G, Artuch R, García-Cazorla A, O'Callaghan M, Sykut-Cegielska J, Campistol J, Moreno-Lozano PJ, Oud MM, Wevers RA, Lefeber DJ, Esteve-Codina A, Yepez VA, Gagneur J, Wortmann SB, Prokisch H, Ribes A, García-Villoria J, Tort F. Genome and RNA sequencing were essential to reveal cryptic intronic variants associated to defective ATP6AP1 mRNA processing. Mol Genet Metab 2024; 142:108511. [PMID: 38878498 DOI: 10.1016/j.ymgme.2024.108511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 05/28/2024] [Accepted: 05/29/2024] [Indexed: 07/05/2024]
Abstract
The diagnosis of Mendelian disorders has notably advanced with integration of whole exome and genome sequencing (WES and WGS) in clinical practice. However, challenges in variant interpretation and uncovered variants by WES still leave a substantial percentage of patients undiagnosed. In this context, integrating RNA sequencing (RNA-seq) improves diagnostic workflows, particularly for WES inconclusive cases. Additionally, functional studies are often necessary to elucidate the impact of prioritized variants on gene expression and protein function. Our study focused on three unrelated male patients (P1-P3) with ATP6AP1-CDG (congenital disorder of glycosylation), presenting with intellectual disability and varying degrees of hepatopathy, glycosylation defects, and an initially inconclusive diagnosis through WES. Subsequent RNA-seq was pivotal in identifying the underlying genetic causes in P1 and P2, detecting ATP6AP1 underexpression and aberrant splicing. Molecular studies in fibroblasts confirmed these findings and identified the rare intronic variants c.289-233C > T and c.289-289G > A in P1 and P2, respectively. Trio-WGS also revealed the variant c.289-289G > A in P3, which was a de novo change in both patients. Functional assays expressing the mutant alleles in HAP1 cells demonstrated the pathogenic impact of these variants by reproducing the splicing alterations observed in patients. Our study underscores the role of RNA-seq and WGS in enhancing diagnostic rates for genetic diseases such as CDG, providing new insights into ATP6AP1-CDG molecular bases by identifying the first two deep intronic variants in this X-linked gene. Additionally, our study highlights the need to integrate RNA-seq and WGS, followed by functional validation, in routine diagnostics for a comprehensive evaluation of patients with an unidentified molecular etiology.
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Affiliation(s)
- Blai Morales-Romero
- Section of Inborn Errors of Metabolism-IBC, Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, ISCIII, Barcelona, Spain.
| | - Gerard Muñoz-Pujol
- Section of Inborn Errors of Metabolism-IBC, Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, ISCIII, Barcelona, Spain.
| | - Rafael Artuch
- Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, CIBERER, Esplugues de Llobregat, Barcelona, Spain.
| | - Angels García-Cazorla
- Neurology Department, Hospital Sant Joan de Déu, Institut de Recerca Hospital Sant Joan de Déu, CIBERER and MetabERN, Esplugues de Llobregat, Barcelona, Spain.
| | - Mar O'Callaghan
- Neurology Department, Hospital Sant Joan de Déu, Institut de Recerca Hospital Sant Joan de Déu, CIBERER and MetabERN, Esplugues de Llobregat, Barcelona, Spain.
| | - Jolanta Sykut-Cegielska
- Department of Inborn Errors of Metabolism and Pediatrics, Institute of Mother and Child, Warsaw, Poland
| | - Jaume Campistol
- Neurology Department, Hospital Sant Joan de Déu, Institut de Recerca Hospital Sant Joan de Déu, CIBERER and MetabERN, Esplugues de Llobregat, Barcelona, Spain.
| | - Pedro Juan Moreno-Lozano
- Inherited Metabolic Diseases and Muscle Disorders' Research Group, Department of Internal Medicine, Hospital Clinic de Barcelona, IDIBAPS, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
| | - Machteld M Oud
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Ron A Wevers
- Department of Human Genetics, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, the Netherlands; United for Metabolic Diseases, The Netherlands.
| | - Dirk J Lefeber
- Department of Human Genetics, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Anna Esteve-Codina
- Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
| | - Vicente A Yepez
- Institute of Human Genetics, School of Medicine, Technical University of Munich, 81675 Munich, Germany; TUM School of Computation, Information and Technology, Technical University of Munich, 85748 Garching, Germany.
| | - Julien Gagneur
- Institute of Human Genetics, School of Medicine, Technical University of Munich, 81675 Munich, Germany; TUM School of Computation, Information and Technology, Technical University of Munich, 85748 Garching, Germany.
| | - Saskia B Wortmann
- University Children's Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria; Amalia Children's Hospital, Department of Pediatrics, Radboudumc, Nijmegen, the Netherlands.
| | - Holger Prokisch
- Institute of Human Genetics, School of Medicine, Technical University of Munich, 81675 Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
| | - Antonia Ribes
- Section of Inborn Errors of Metabolism-IBC, Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, ISCIII, Barcelona, Spain.
| | - Judit García-Villoria
- Section of Inborn Errors of Metabolism-IBC, Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, ISCIII, Barcelona, Spain.
| | - Frederic Tort
- Section of Inborn Errors of Metabolism-IBC, Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, ISCIII, Barcelona, Spain.
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Wang WC, Hou TC, Kuo CY, Lai YC. Amplifications of EVX2 and HOXD9-HOXD13 on 2q31 in mature cystic teratomas of the ovary identified by array comparative genomic hybridization may explain teratoma characteristics in chondrogenesis and osteogenesis. J Ovarian Res 2024; 17:129. [PMID: 38907278 PMCID: PMC11193297 DOI: 10.1186/s13048-024-01458-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 06/16/2024] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND Teratomas are a common type of germ cell tumor. However, only a few reports on their genomic constitution have been published. The study of teratomas may provide a better understanding of their stepwise differentiation processes and molecular bases, which could prove useful for the development of tissue-engineering technologies. METHODS In the present study, we analyzed the copy number aberrations of nine ovarian mature cystic teratomas using array comparative genomic hybridization in an attempt to reveal their genomic aberrations. RESULTS The many chromosomal aberrations observed on array comparative genomic hybridization analysis reveal the complex genetics of this tumor. Amplifications and deletions of large DNA fragments were observed in some samples, while amplifications of EVX2 and HOXD9-HOXD13 on 2q31.1, NDUFV1 on 11q13.2, and RPL10, SNORA70, DNASE1L1, TAZ, ATP6AP1, and GDI1 on Xq28 were found in all nine mature cystic teratomas. CONCLUSIONS Our results indicated that amplifications of these genes may play an important etiological role in teratoma formation. Moreover, amplifications of EVX2 and HOXD9-HOXD13 on 2q31.1, found on array comparative genomic hybridization, may help to explain the characteristics of teratomas in chondrogenesis and osteogenesis.
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Affiliation(s)
- Wen-Chung Wang
- Department of Obstetrics and Gynecology, Jen-Ai Hospital, Taichung, Taiwan
| | - Tai-Cheng Hou
- Department of Pathology, Jen-Ai Hospital, Taichung, Taiwan
| | - Chen-Yun Kuo
- Department of Pathology, Jen-Ai Hospital, Taichung, Taiwan
| | - Yen-Chein Lai
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, No.110, Sec. 1, Chien Kuo N. Road, Taichung, 402, Taiwan, R.O.C..
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.
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15
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Szaflarska A, Lenart M, Rutkowska-Zapała M, Siedlar M. Clinical and experimental treatment of primary humoral immunodeficiencies. Clin Exp Immunol 2024; 216:120-131. [PMID: 38306460 PMCID: PMC11036112 DOI: 10.1093/cei/uxae008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/13/2023] [Accepted: 01/31/2024] [Indexed: 02/04/2024] Open
Abstract
Selective IgA deficiency (sIgAD), common variable immunodeficiency (CVID), and transient hypogammaglobulinemia of infancy (THI) are the most frequent forms of primary antibody deficiencies. Difficulties in initial diagnosis, especially in the early childhood, the familiar occurrence of these diseases, as well as the possibility of progression to each other suggest common cellular and molecular patomechanism and a similar genetic background. In this review, we discuss both similarities and differences of these three humoral immunodeficiencies, focusing on current and novel therapeutic approaches. We summarize immunoglobulin substitution, antibiotic prophylaxis, treatment of autoimmune diseases, and other common complications, i.e. cytopenias, gastrointestinal complications, and granulomatous disease. We discuss novel therapeutic approaches such as allogenic stem cell transplantation and therapies targeting-specific proteins, dependent on the patient's genetic defect. The diversity of possible therapeutics models results from a great heterogeneity of the disease variants, implying the need of personalized medicine approach as a future of primary humoral immunodeficiencies treatment.
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Affiliation(s)
- Anna Szaflarska
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, Cracow, Poland
- Deparment of Clinical Immunology, University Children’s Hospital, Wielicka 265, Cracow, Poland
| | - Marzena Lenart
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, Cracow, Poland
- Deparment of Clinical Immunology, University Children’s Hospital, Wielicka 265, Cracow, Poland
| | - Magdalena Rutkowska-Zapała
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, Cracow, Poland
- Deparment of Clinical Immunology, University Children’s Hospital, Wielicka 265, Cracow, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, Cracow, Poland
- Deparment of Clinical Immunology, University Children’s Hospital, Wielicka 265, Cracow, Poland
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16
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Nazeer B, Khawar MB, Khalid MU, Hamid SE, Rafiq M, Abbasi MH, Sheikh N, Ali A, Fatima H, Ahmad S. Emerging role of lipophagy in liver disorders. Mol Cell Biochem 2024; 479:1-11. [PMID: 36943663 DOI: 10.1007/s11010-023-04707-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/10/2023] [Indexed: 03/23/2023]
Abstract
Lipophagy is a selective degradation of lipids by a lysosomal-mediated pathway, and dysregulation of lipophagy is linked with the pathological hallmark of many liver diseases. Downregulation of lipophagy in liver cells results in abnormal accumulation of LDs (Lipid droplets) in hepatocytes which is a characteristic feature of several liver pathologies such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Contrarily, upregulation of lipophagy in activated hepatic stellate cells (HSCs) is associated with hepatic fibrosis and cirrhosis. Lipid metabolism reprogramming in violent cancer cells contributes to the progression of liver cancer. In this review, we have summarized the recent studies focusing on various components of the lipophagic machinery that can be modulated for their potential role as therapeutic agents against a wide range of liver diseases.
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Affiliation(s)
- Bismillah Nazeer
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Muhammad Babar Khawar
- Applied Molecular Biology and Biomedicine Lab, Department of Zoology, University of Narowal, Narowal, Pakistan.
| | - Muhammad Usman Khalid
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Syeda Eisha Hamid
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Mussarat Rafiq
- Cell and Molecular Biology Lab, Institute of Zoology, University of the Punjab, Lahore, Pakistan
| | | | - Nadeem Sheikh
- Cell and Molecular Biology Lab, Institute of Zoology, University of the Punjab, Lahore, Pakistan.
| | - Ahmad Ali
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Hooriya Fatima
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Sadia Ahmad
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
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17
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Li K, Xiao J, Ling Z, Luo T, Xiong J, Chen Q, Dong L, Wang Y, Wang X, Jiang Z, Xia L, Yu Z, Hua R, Guo R, Tang D, Lv M, Lian A, Li B, Zhao G, He X, Xia K, Cao Y, Li J. Prioritizing de novo potential non-canonical splicing variants in neurodevelopmental disorders. EBioMedicine 2024; 99:104928. [PMID: 38113761 PMCID: PMC10767160 DOI: 10.1016/j.ebiom.2023.104928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 11/30/2023] [Accepted: 12/05/2023] [Indexed: 12/21/2023] Open
Abstract
BACKGROUND Genomic variants outside of the canonical splicing site (±2) may generate abnormal mRNA splicing, which are defined as non-canonical splicing variants (NCSVs). However, the clinical interpretation of NCSVs in neurodevelopmental disorders (NDDs) is largely unknown. METHODS We investigated the contribution of NCSVs to NDDs from 345,787 de novo variants (DNVs) in 47,574 patients with NDDs. We performed functional enrichment and protein-protein interaction analysis to assess the association between genes carrying prioritised NCSVs and NDDs. Minigene was used to validate the impact of NCSVs on mRNA splicing. FINDINGS We observed significantly more NCSVs (p = 0.02, odds ratio [OR] = 2.05) among patients with NDD than in controls. Both canonical splicing variants (CSVs) and NCSVs contributed to an equal proportion of patients with NDD (0.76% vs. 0.82%). The candidate genes carrying NCSVs were associated with glutamatergic synapse and chromatin remodelling. Minigene successfully validated 59 of 79 (74.68%) NCSVs that led to abnormal splicing in 40 candidate genes, and 9 of the genes (ARID1B, KAT6B, TCF4, SMARCA2, SHANK3, PDHA1, WDR45, SCN2A, SYNGAP1) harboured recurrent NCSVs with the same variant present in more than two unrelated patients with NDD. Moreover, 36 of 59 (61.02%) NCSVs are novel clinically relevant variants, including 34 unreported and 2 clinically conflicting interpretations or of uncertain significance NCSVs in the ClinVar database. INTERPRETATION This study highlights the common pathology and clinical importance of NCSVs in unsolved patients with NDD. FUNDING The present study was funded by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, the Hunan Youth Science and Technology Innovation Talent Project, the Provincial Natural Science Foundation of Hunan, The Scientific Research Program of FuRong laboratory, and the Natural Science Project of the University of Anhui Province.
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Affiliation(s)
- Kuokuo Li
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Jifang Xiao
- Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
| | - Zhengbao Ling
- Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Tengfei Luo
- Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Jingyu Xiong
- Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Qian Chen
- Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
| | - Lijie Dong
- Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
| | - Yijing Wang
- Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
| | - Xiaomeng Wang
- Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
| | - Zhaowei Jiang
- Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Lu Xia
- Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Zhen Yu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Rong Hua
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Rui Guo
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Dongdong Tang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Mingrong Lv
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Aojie Lian
- National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China
| | - Bin Li
- Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
| | - GuiHu Zhao
- Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
| | - Xiaojin He
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China; Anhui Provincial Human Sperm Bank, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
| | - Kun Xia
- Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
| | - Yunxia Cao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China.
| | - Jinchen Li
- Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China.
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Xiong YM, Zhou F, Zhou JW, Liu F, Zhou SQ, Li B, Liu ZJ, Qin Y. Aberrant Expressions of PSMD14 in Tumor Tissue are the Potential Prognostic Biomarkers for Hepatocellular Carcinoma after Curative Resection. Curr Genomics 2023; 24:368-384. [PMID: 38327651 PMCID: PMC10845065 DOI: 10.2174/0113892029277262231108105441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/05/2023] [Accepted: 10/06/2023] [Indexed: 02/09/2024] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) has a high mortality rate, with curative resection being the primary treatment. However, HCC patients have a large possibility of recurrence within 5 years after curative resection. Methods Thus, identifying biomarkers to predict recurrence is crucial. In our study, we analyzed data from CCLE, GEO, and TCGA, identifying eight oncogenes associated with HCC. Subsequently, the expression of 8 genes was tested in 5 cases of tumor tissues and the adjacent non-tumor tissues. Then ATP6AP1, PSMD14 and HSP90AB1 were selected to verify the expression in 63 cases of tumor tissues and the adjacent non-tumor tissues. The results showed that ATP6AP1, PSMD14, HSP90AB1 were generally highly expressed in tumor tissues. A five-year follow-up of the 63 clinical cases, combined with Kaplan-Meier Plotter's relapse-free survival (RFS) analysis, found a significant correlation between PSMD14 expression and recurrence in HCC patients. Subsequently, we analyzed the PSMD14 mutations and found that the PSMD14 gene mutations can lead to a shorter disease-free survival time for HCC patients. Results The results of enrichment analysis indicated that the differentially expressed genes related to PSMD14 are mainly enriched in the signal release pathway. Conclusion In conclusion, our research showed that PSMD14 might be related to recurrence in HCC patients, and the expression of PSMD14 in tumor tissue might be a potential prognostic biomarker after tumor resection in HCC patients.
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Affiliation(s)
- Yi-Mei Xiong
- Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610 041, China
| | - Fang Zhou
- Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610 041, China
| | - Jia-Wen Zhou
- Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610 041, China
| | - Fei Liu
- Division of Liver Transplantation, Department of Surgery, West China Hospital, Sichuan University, Chengdu, 610 041, China
| | - Si-Qi Zhou
- Division of Liver Transplantation, Department of Surgery, West China Hospital, Sichuan University, Chengdu, 610 041, China
| | - Bo Li
- Division of Liver Transplantation, Department of Surgery, West China Hospital, Sichuan University, Chengdu, 610 041, China
| | - Zhong-Jian Liu
- Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610 041, China
| | - Yang Qin
- Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610 041, China
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19
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Liu S, Wang Y, Weng L, Wu J, Man Q, Xia Y, Huang LH. Water-stable hydrophilic metal organic framework composite for the recognition of N-glycopeptides during diabetes progression by mass spectrometry. Mikrochim Acta 2023; 191:11. [PMID: 38055058 DOI: 10.1007/s00604-023-06052-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 10/16/2023] [Indexed: 12/07/2023]
Abstract
A hydrophilic Al-MOFs composite was prepared using cheap and available reagents in water via a suitable large-scale production, an economical and environment-friendly method for capturing N-glycopeptides. The prepared Al-MOFs composite with high hydrolytically stable and hydrophilic 1D channels exhibits an ultralow detection limit (0.5 fmol/μL), and excellent reusability (at least 10 cycles) in the capture of N-glycopeptides from standard bio-samples. Interestingly, the Al-MOFs composite also shows remarkable performance in practical applications, where 300 N-glycopeptides ascribed to 124 glycoproteins were identified in 1 µL human serum and were successfully applied in profiling the differences of N-glycopeptides during diabetes progression. Moreover, 12 specific glycoproteins used as biomarkers to accurately distinguish the progression of diabetes are identified. The present work provides a potential commercial method for large-scale glycoproteomics research in complex clinical samples while offering new guidance for the precise diagnosis of diabetes progression.
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Affiliation(s)
- Shuangshuang Liu
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Yang Wang
- Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200438, China
| | - Lingxiao Weng
- Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200438, China
| | - Jiaqi Wu
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Qiuhong Man
- Department of Clinical Laboratory, Shanghai Fourth People's Hospital, Tongji University, Shanghai, 200434, China.
| | - Yan Xia
- Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200438, China.
- School of Materials Science and Engineering, NingboTech University, Ningbo, 315100, China.
| | - Li-Hao Huang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
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20
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Cocchiararo I, Cattaneo O, Rajendran J, Chabry F, Cornut M, Soldati H, Bigot A, Mamchaoui K, Gibertini S, Bouche A, Ham DJ, Laumonier T, Prola A, Castets P. Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis. Hum Mol Genet 2023; 32:3374-3389. [PMID: 37756622 PMCID: PMC10695681 DOI: 10.1093/hmg/ddad164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/23/2023] [Accepted: 09/21/2023] [Indexed: 09/29/2023] Open
Abstract
Defective lysosomal acidification is responsible for a large range of multi-systemic disorders associated with impaired autophagy. Diseases caused by mutations in the VMA21 gene stand as exceptions, specifically affecting skeletal muscle (X-linked Myopathy with Excessive Autophagy, XMEA) or liver (Congenital Disorder of Glycosylation). VMA21 chaperones vacuolar (v-) ATPase assembly, which is ubiquitously required for proper lysosomal acidification. The reason VMA21 deficiencies affect specific, but divergent tissues remains unknown. Here, we show that VMA21 encodes a yet-unreported long protein isoform, in addition to the previously described short isoform, which we name VMA21-120 and VMA21-101, respectively. In contrast to the ubiquitous pattern of VMA21-101, VMA21-120 was predominantly expressed in skeletal muscle, and rapidly up-regulated upon differentiation of mouse and human muscle precursors. Accordingly, VMA21-120 accumulated during development, regeneration and denervation of mouse skeletal muscle. In contrast, neither induction nor blockade of autophagy, in vitro and in vivo, strongly affected VMA21 isoform expression. Interestingly, VMA21-101 and VMA21-120 both localized to the sarcoplasmic reticulum of muscle cells, and interacted with the v-ATPase. While VMA21 deficiency impairs autophagy, VMA21-101 or VMA21-120 overexpression had limited impact on autophagic flux in muscle cells. Importantly, XMEA-associated mutations lead to both VMA21-101 deficiency and loss of VMA21-120 expression. These results provide important insights into the clinical diversity of VMA21-related diseases and uncover a muscle-specific VMA21 isoform that potently contributes to XMEA pathogenesis.
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Affiliation(s)
- Ilaria Cocchiararo
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
| | - Olivia Cattaneo
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
| | - Jayasimman Rajendran
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
| | - Florent Chabry
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
| | - Mélanie Cornut
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
| | - Hadrien Soldati
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
| | - Anne Bigot
- Centre de Recherche en Myologie, Inserm, Institut de Myologie, Sorbonne Université, 47 Bd de l'Hôpital, 75013 Paris, France
| | - Kamel Mamchaoui
- Centre de Recherche en Myologie, Inserm, Institut de Myologie, Sorbonne Université, 47 Bd de l'Hôpital, 75013 Paris, France
| | - Sara Gibertini
- Neuromuscular Diseases and Neuroimmunology Unit, Muscle Cell Biology Lab, Fondazione IRCCS Istituto Neurologico “C. Besta”, Via Amadeo 42, 20133 Milano, Italy
| | - Axelle Bouche
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
- Department of Orthopaedic Surgery, Geneva University Hospitals and Faculty of Medicine, University Medical Center, 1 rue Michel Servet, 1211, Geneva, Switzerland
| | - Daniel J Ham
- Biozentrum, University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland
| | - Thomas Laumonier
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
- Department of Orthopaedic Surgery, Geneva University Hospitals and Faculty of Medicine, University Medical Center, 1 rue Michel Servet, 1211, Geneva, Switzerland
| | - Alexandre Prola
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
| | - Perrine Castets
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland
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21
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Liu C, Zhang S, Xue J, Zhang H, Yin J. Evaluation of PEN2-ATP6AP1 axis as an antiparasitic target for metformin based on phylogeny analysis and molecular docking. Mol Biochem Parasitol 2023; 255:111580. [PMID: 37473813 DOI: 10.1016/j.molbiopara.2023.111580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 07/09/2023] [Accepted: 07/17/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND Metformin (Met), the first-line drug used in the treatment for type 2 diabetes mellitus, is effective against a variety of parasites. However, the molecular target of Met at clinical dose against various parasites remains unclear. Recently, low-dose Met (clinical dose) has been reported to directly bind PEN2 (presenilin enhancer protein 2) and initiate the lysosomal glucose-sensing pathway for AMPK activation via ATP6AP1 (V-type proton ATPase subunit S1), rather than perturbing AMP/ATP levels. METHODS To explore the possibility of PEN2-ATP6AP1 axis as a drug target of Met for the treatment of parasitic diseases, we identified and characterized orthologs of PEN2 and ATP6AP1 genes in parasites, by constructing phylogenetic trees, analyzing protein sequences and predicting interactions between Met and parasite PEN2. RESULTS The results showed that PEN2 and ATP6AP1 genes are only found together in a few of parasite species in the cestoda and nematoda groups. Indicated by molecular simulation, Met might function by interacting with PEN2 on V37/W38/E5 (Trichinella spiralis) with similar binding energy, and on F35/S39 (Caenorhabditis elegans) with higher binding energy, comparing to human PEN2. Hence, these results indicated that only the T. spiralis PEN2-ATP6AP1 axis has the potential to be the direct target of low-concentration Met. Together with contribution of host cells including immune cells in vivo, T. spiralis PEN2-ATP6AP1 axis might play roles in reducing parasite load at low-concentration Met. However, the mechanisms of low-concentration Met on other parasitic infections might be mainly achieved by regulating host cells, rather than directly targeting PEN2-ATP6AP1 axis. CONCLUSIONS These findings revealed the potential mechanisms by which Met treats various parasitic diseases, and shed new light on the development of antiparasitic drugs.
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Affiliation(s)
- Congshan Liu
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
| | - Shangrui Zhang
- Henan Medical College, No. 8 Shuanghu Avenue, Longhu Town, Xinzheng, Zhengzhou City 451191, Henan Province, China
| | - Jian Xue
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
| | - Haobing Zhang
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
| | - Jianhai Yin
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China.
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22
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van Strien J, Evers F, Lutikurti M, Berendsen SL, Garanto A, van Gemert GJ, Cabrera-Orefice A, Rodenburg RJ, Brandt U, Kooij TWA, Huynen MA. Comparative Clustering (CompaCt) of eukaryote complexomes identifies novel interactions and sheds light on protein complex evolution. PLoS Comput Biol 2023; 19:e1011090. [PMID: 37549177 PMCID: PMC10434966 DOI: 10.1371/journal.pcbi.1011090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 08/17/2023] [Accepted: 07/10/2023] [Indexed: 08/09/2023] Open
Abstract
Complexome profiling allows large-scale, untargeted, and comprehensive characterization of protein complexes in a biological sample using a combined approach of separating intact protein complexes e.g., by native gel electrophoresis, followed by mass spectrometric analysis of the proteins in the resulting fractions. Over the last decade, its application has resulted in a large collection of complexome profiling datasets. While computational methods have been developed for the analysis of individual datasets, methods for large-scale comparative analysis of complexomes from multiple species are lacking. Here, we present Comparative Clustering (CompaCt), that performs fully automated integrative analysis of complexome profiling data from multiple species, enabling systematic characterization and comparison of complexomes. CompaCt implements a novel method for leveraging orthology in comparative analysis to allow systematic identification of conserved as well as taxon-specific elements of the analyzed complexomes. We applied this method to a collection of 53 complexome profiles spanning the major branches of the eukaryotes. We demonstrate the ability of CompaCt to robustly identify the composition of protein complexes, and show that integrated analysis of multiple datasets improves characterization of complexes from specific complexome profiles when compared to separate analyses. We identified novel candidate interactors and complexes in a number of species from previously analyzed datasets, like the emp24, the V-ATPase and mitochondrial ATP synthase complexes. Lastly, we demonstrate the utility of CompaCt for the automated large-scale characterization of the complexome of the mosquito Anopheles stephensi shedding light on the evolution of metazoan protein complexes. CompaCt is available from https://github.com/cmbi/compact-bio.
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Affiliation(s)
- Joeri van Strien
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Felix Evers
- Medical Microbiology, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Madhurya Lutikurti
- Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Stijn L. Berendsen
- Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Alejandro Garanto
- Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Geert-Jan van Gemert
- Medical Microbiology, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Alfredo Cabrera-Orefice
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Richard J. Rodenburg
- Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Pediatrics, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Ulrich Brandt
- Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
- Radboud Center for Mitochondrial Medicine (RCMM), Radboud University Medical Center, Nijmegen, the Netherlands
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Taco W. A. Kooij
- Medical Microbiology, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martijn A. Huynen
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, the Netherlands
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23
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Ameratunga R, Edwards ESJ, Lehnert K, Leung E, Woon ST, Lea E, Allan C, Chan L, Steele R, Longhurst H, Bryant VL. The Rapidly Expanding Genetic Spectrum of Common Variable Immunodeficiency-Like Disorders. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1646-1664. [PMID: 36796510 DOI: 10.1016/j.jaip.2023.01.048] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/21/2023] [Accepted: 01/27/2023] [Indexed: 02/16/2023]
Abstract
The understanding of common variable immunodeficiency disorders (CVID) is in evolution. CVID was previously a diagnosis of exclusion. New diagnostic criteria have allowed the disorder to be identified with greater precision. With the advent of next-generation sequencing (NGS), it has become apparent that an increasing number of patients with a CVID phenotype have a causative genetic variant. If a pathogenic variant is identified, these patients are removed from the overarching diagnosis of CVID and are deemed to have a CVID-like disorder. In populations where consanguinity is more prevalent, the majority of patients with severe primary hypogammaglobulinemia will have an underlying inborn error of immunity, usually an early-onset autosomal recessive disorder. In nonconsanguineous societies, pathogenic variants are identified in approximately 20% to 30% of patients. These are often autosomal dominant mutations with variable penetrance and expressivity. To add to the complexity of CVID and CVID-like disorders, some genetic variants such as those in TNFSF13B (transmembrane activator calcium modulator cyclophilin ligand interactor) predispose to, or enhance, disease severity. These variants are not causative but can have epistatic (synergistic) interactions with more deleterious mutations to worsen disease severity. This review is a description of the current understanding of genes associated with CVID and CVID-like disorders. This information will assist clinicians in interpreting NGS reports when investigating the genetic basis of disease in patients with a CVID phenotype.
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Affiliation(s)
- Rohan Ameratunga
- Department of Clinical immunology, Auckland Hospital, Auckland, New Zealand; Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand; Department of Molecular Medicine and Pathology, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
| | - Emily S J Edwards
- The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, and Allergy and Clinical Immunology Laboratory, Department of Immunology, Monash University, Melbourne, VIC, Australia
| | - Klaus Lehnert
- Applied Translational Genetics Group, School of Biological Sciences, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre, School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Euphemia Leung
- Auckland Cancer Society Research Centre, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - See-Tarn Woon
- Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand
| | - Edward Lea
- Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand
| | - Caroline Allan
- Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand
| | - Lydia Chan
- Department of Clinical immunology, Auckland Hospital, Auckland, New Zealand
| | - Richard Steele
- Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand; Department of Respiratory Medicine, Wellington Hospital, Wellington, New Zealand
| | - Hilary Longhurst
- Department of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Vanessa L Bryant
- Department of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, VIC, Australia
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24
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Semenova N, Shatokhina O, Shchagina O, Kamenec E, Marakhonov A, Degtyareva A, Taran N, Strokova T. Clinical Presentation of a Patient with a Congenital Disorder of Glycosylation, Type IIs ( ATP6AP1), and Liver Transplantation. Int J Mol Sci 2023; 24:ijms24087449. [PMID: 37108612 PMCID: PMC10140882 DOI: 10.3390/ijms24087449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/06/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
The congenital disorder of glycosylation type IIs (ATP6AP1-CDG; OMIM# 300972) is a rare X-linked recessive complex syndrome characterized by liver dysfunction, recurrent bacterial infections, hypogammaglobulinemia, and defective glycosylation of serum proteins. Here, we examine the case of a 1-year-old male patient of Buryat origin, who presented with liver dysfunction. At the age of 3 months, he was hospitalized with jaundice and hepatosplenomegaly. Whole-exome sequencing identified the ATP6AP1 gene missense variant NM_001183.6:c.938A>G (p.Tyr313Cys) in the hemizygous state, which was previously reported in a patient with immunodeficiency type 47. At the age of 10 months, the patient successfully underwent orthotopic liver transplantation. After the transplantation, the use of Tacrolimus entailed severe adverse effect (colitis with perforation). Replacing Tacrolimus with Everolimus led to improvement. Previously reported patients demonstrated abnormal N- and O-glycosylation, but these data were collected without any specific treatment. In contrast, in our patient, isoelectric focusing (IEF) of serum transferrin was performed only after the liver transplant and showed a normal IEF pattern. Thus, liver transplantation could be a curative option for patients with ATP6AP1-CDG.
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Affiliation(s)
| | | | - Olga Shchagina
- Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Elena Kamenec
- Research Centre for Medical Genetics, 115522 Moscow, Russia
| | | | - Anna Degtyareva
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after V.I. Kulakov, Ministry of Health of the Russian Federation, 127994 Moscow, Russia
- Department of Neonatology, I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia
| | - Natalia Taran
- Federal Research Center of Nutrition and Biotechnology, 109240 Moscow, Russia
| | - Tatiana Strokova
- Federal Research Center of Nutrition and Biotechnology, 109240 Moscow, Russia
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25
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Hu J, Xu X, Li J, Jiang Y, Hong X, Rexrode KM, Wang G, Hu FB, Zhang H, Karmaus WJ, Wang X, Liang L. Sex differences in the intergenerational link between maternal and neonatal whole blood DNA methylation: a genome-wide analysis in 2 birth cohorts. Clin Epigenetics 2023; 15:51. [PMID: 36966332 PMCID: PMC10040137 DOI: 10.1186/s13148-023-01442-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 02/06/2023] [Indexed: 03/27/2023] Open
Abstract
BACKGROUND The mother-child inheritance of DNA methylation (DNAm) variations could contribute to the inheritance of disease susceptibility across generations. However, no study has investigated patterns of mother-child associations in DNAm at the genome-wide scale. It remains unknown whether there are sex differences in mother-child DNAm associations. RESULTS Using genome-wide DNAm profiling data (721,331 DNAm sites, including 704,552 on autosomes and 16,779 on the X chromosome) of 396 mother-newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant sex differences in mother-newborn correlations in genome-wide DNAm patterns (Spearman's rho = 0.91-0.98; p = 4.0 × 10-8), with female newborns having stronger correlations. Sex differences in correlations were attenuated but remained significant after excluding X-chromosomal DNAm sites (Spearman's rho = 0.91-0.98; p = 0.035). Moreover, 89,267 DNAm sites (12.4% of all analyzed, including 88,051 [12.5% of analyzed] autosomal and 1,216 [7.2% of analyzed] X-chromosomal sites) showed significant mother-newborn associations in methylation levels, and the top autosomal DNAm sites had high heritability than the genome-wide background (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.92). Additionally, significant interactions between newborn sex and methylation levels were observed for 11 X-chromosomal and 4 autosomal DNAm sites that were mapped to genes that have been associated with sex-specific disease/traits or early development (e.g., EFHC2, NXY, ADCYAP1R1, and BMP4). Finally, 18,769 DNAm sites (14,482 [77.2%] on the X chromosome) showed mother-newborn differences in methylation levels that were significantly associated with newborn sex, and the top autosomal DNAm sites had relatively small heritability (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.23). These DNAm sites were mapped to 2,532 autosomal genes and 978 X-chromosomal genes with significant enrichment in pathways involved in neurodegenerative and psychological diseases, development, neurophysiological process, immune response, and sex-specific cancers. Replication analysis in the Isle of Wight birth cohort yielded consistent results. CONCLUSION In two independent birth cohorts, we demonstrated strong mother-newborn correlations in whole blood DNAm on both autosomes and ChrX, and such correlations vary substantially by sex. Future studies are needed to examine to what extent our findings contribute to developmental origins of pediatric and adult diseases with well-observed sex differences.
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Affiliation(s)
- Jie Hu
- Division of Women's Health, Department of Medicine, Bigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building 2, Room 207, Boston, MA, 02115, USA
| | - Xin Xu
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building 2, Room 207, Boston, MA, 02115, USA
| | - Jun Li
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building 2, Room 207, Boston, MA, 02115, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Yu Jiang
- Division of Epidemiology, Biostatistics, & Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
| | - Xiumei Hong
- Center On the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Kathryn M Rexrode
- Division of Women's Health, Department of Medicine, Bigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Guoying Wang
- Center On the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Frank B Hu
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building 2, Room 207, Boston, MA, 02115, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Hongmei Zhang
- Division of Epidemiology, Biostatistics, & Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
| | - Wilfried J Karmaus
- Division of Epidemiology, Biostatistics, & Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
| | - Xiaobin Wang
- Center On the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Liming Liang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building 2, Room 207, Boston, MA, 02115, USA.
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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Alharbi H, Daniel EJP, Thies J, Chang I, Goldner DL, Ng BG, Witters P, Aqul A, Velez-Bartolomei F, Enns GM, Hsu E, Kichula E, Lee E, Lourenco C, Poskanzer SA, Rasmussen S, Saarela K, Wang YM, Raymond KM, Schultz MJ, Freeze HH, Lam C, Edmondson AC, He M. Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association. J Inherit Metab Dis 2023; 46:300-312. [PMID: 36651831 PMCID: PMC10047170 DOI: 10.1002/jimd.12589] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023]
Abstract
ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.
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Affiliation(s)
- Hana Alharbi
- Department of Pediatrics, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Earnest James Paul Daniel
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Jenny Thies
- Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington, USA
| | - Irene Chang
- Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA
| | - Dana L Goldner
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University Medical Center, New York, New York, USA
| | - Bobby G Ng
- Human Genetics Program, Sanford Burnham Prebys, La Jolla, California, USA
| | - Peter Witters
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Center for Metabolic Diseases, University Hospital Leuven, Leuven, Belgium
- Department of Development and Regeneration, Faculty of Medicine, KU Leuven, University Hospitals Leuven, Leuven, Belgium
| | - Amal Aqul
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Texas Southwestern/Children's Medical Center, Dallas, Texas, USA
| | - Frances Velez-Bartolomei
- Genetics Section, San Jorge Children and Women's Hospital in San Juan, San Juan, Puerto Rico, USA
- Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital and Stanford University, Stanford, California, USA
| | - Gregory M Enns
- Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital and Stanford University, Stanford, California, USA
| | - Evelyn Hsu
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, Washington, USA
| | - Elizabeth Kichula
- Division of Neurology, Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Esther Lee
- Genetic Services, Kaiser Permanente of Washington, Seattle, Washington, USA
| | - Charles Lourenco
- Faculdade de Medicina de São José do Rio Preto (FAMERP), São Jose do Rio Preto - São Paulo, Brazil
- Personalized Medicine area, Special Education Sector at DLE/Grupo Pardini, Belo Horizonte - MG, Brazil
| | - Sheri A Poskanzer
- St. Luke's Health System, Boise, Idaho, USA
- Department of Pediatrics, School of Medicine, University of Washington, Seattle, Washington, USA
| | - Sara Rasmussen
- Transplant Center, Department of Surgery, Seattle Children's Hospital University of Washington School of Medicine Seattle, Seattle, Washington, USA
| | - Katelyn Saarela
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, Washington, USA
| | - YunZu M Wang
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA
| | - Kimiyo M Raymond
- Department of Laboratory Medicine and Pathology, Laboratory Genetics and Genomics, Mayo Clinic, Rochester, Minnesota, USA
| | - Matthew J Schultz
- Department of Laboratory Medicine and Pathology, Laboratory Genetics and Genomics, Mayo Clinic, Rochester, Minnesota, USA
| | - Hudson H Freeze
- Human Genetics Program, Sanford Burnham Prebys, La Jolla, California, USA
| | - Christina Lam
- Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA
| | - Andrew C Edmondson
- Department of Pediatrics, Division of Human Genetics, Section of Metabolism, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Miao He
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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27
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Dang Do AN, Chang IJ, Jiang X, Wolfe LA, Ng BG, Lam C, Schnur RE, Allis K, Hansikova H, Ondruskova N, O’Connor SD, Sanchez-Valle A, Vollo A, Wang RY, Wolfenson Z, Perreault J, Ory DS, Freeze HH, Merritt JL, Porter FD. Elevated oxysterol and N-palmitoyl-O-phosphocholineserine levels in congenital disorders of glycosylation. J Inherit Metab Dis 2023; 46:326-334. [PMID: 36719165 PMCID: PMC10023375 DOI: 10.1002/jimd.12595] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/19/2023] [Accepted: 01/23/2023] [Indexed: 02/01/2023]
Abstract
Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.
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Affiliation(s)
- An N. Dang Do
- Office of the Clinical Director, NICHD, NIH, Bethesda, MD, USA
- Correspondence An Ngoc Dang Do, MD PhD, , 10 Center Drive, MSC 1103, Bethesda, MD 20892
| | - Irene J. Chang
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Xutian Jiang
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Lynne A. Wolfe
- Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, MD, USA
| | - Bobby G. Ng
- Human Genetics Program, Sanford Children’s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Christina Lam
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
- Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, USA
| | | | | | - Hana Hansikova
- Department of Pediatrics and Inherited Metabolic Disorders, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Nina Ondruskova
- Department of Pediatrics and Inherited Metabolic Disorders, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Shawn D. O’Connor
- Department of Pediatrics, Washington University School of Medicine in St. Louis, Saint Louis, MO, USA
| | | | - Arve Vollo
- Department of Paediatrics, Sykehuset Ostfold HF, Fredrikstad, Norway
| | - Raymond Y. Wang
- Children’s Hospital of Orange County, Orange County, CA, USA
- University of California-Irvine School of Medicine, Irvine, CA, USA
| | - Zoe Wolfenson
- Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, MD, USA
| | - John Perreault
- Office of the Clinical Director, NICHD, NIH, Bethesda, MD, USA
| | - Daniel S. Ory
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Hudson H. Freeze
- Human Genetics Program, Sanford Children’s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - J Lawrence Merritt
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Forbes D. Porter
- Section on Molecular Dysmorphology, NICHD, NIH, Bethesda, MD, USA
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Patterson AR, Needle GA, Sugiura A, Chi C, Steiner KK, Fisher EL, Robertson GL, Bodnya C, Markle JG, Gama V, Rathmell JC. Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.24.525419. [PMID: 36747715 PMCID: PMC9900827 DOI: 10.1101/2023.01.24.525419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and the de novo hexosamine synthesis enzyme, Gfpt1 , are critical for T cell expansion and function. Interestingly, Gfpt1 -deficient T H 1 cells were more affected than T H 17 cells, which had increased Nagk for salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factor Bcl11b promotes CD4 + T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders. HIGHLIGHTS Inborn errors of immunity and metabolism have greater overlap than previously known Gfpt1 deficiency causes an IEM but also selectively regulates T cell subset fate Loss of Bcl11b causes a T cell deficiency IEI but also harms mitochondrial function Many IEM may have immune defects and IEI may be driven by metabolic mechanisms.
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SARS-CoV-2 Pattern Provides a New Scoring System and Predicts the Prognosis and Immune Therapeutic Response in Glioma. Cells 2022; 11:cells11243997. [PMID: 36552760 PMCID: PMC9777143 DOI: 10.3390/cells11243997] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/05/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Glioma is the most common primary malignancy of the adult central nervous system (CNS), with a poor prognosis and no effective prognostic signature. Since late 2019, the world has been affected by the rapid spread of SARS-CoV-2 infection. Research on SARS-CoV-2 is flourishing; however, its potential mechanistic association with glioma has rarely been reported. The aim of this study was to investigate the potential correlation of SARS-CoV-2-related genes with the occurrence, progression, prognosis, and immunotherapy of gliomas. METHODS SARS-CoV-2-related genes were obtained from the human protein atlas (HPA), while transcriptional data and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Glioma samples were collected from surgeries with the knowledge of patients. Differentially expressed genes were then identified and screened, and seven SARS-CoV-2 related genes were generated by LASSO regression analysis and uni/multi-variate COX analysis. A prognostic SARS-CoV-2-related gene signature (SCRGS) was then constructed based on these seven genes and validated in the TCGA validation cohort and CGGA cohort. Next, a nomogram was established by combining critical clinicopathological data. The correlation between SCRGS and glioma related biological processes was clarified by Gene set enrichment analysis (GSEA). In addition, immune infiltration and immune score, as well as immune checkpoint expression and immune escape, were further analyzed to assess the role of SCRGS in glioma-associated immune landscape and the responsiveness of immunotherapy. Finally, the reliability of SCRGS was verified by quantitative real-time polymerase chain reaction (qRT-PCR) on glioma samples. RESULTS The prognostic SCRGS contained seven genes, REEP6, CEP112, LARP4B, CWC27, GOLGA2, ATP6AP1, and ERO1B. Patients were divided into high- and low-risk groups according to the median SARS-CoV-2 Index. Overall survival was significantly worse in the high-risk group than in the low-risk group. COX analysis and receiver operating characteristic (ROC) curves demonstrated excellent predictive power for SCRGS for glioma prognosis. In addition, GSEA, immune infiltration, and immune scores indicated that SCRGS could potentially predict the tumor microenvironment, immune infiltration, and immune response in glioma patients. CONCLUSIONS The SCRGS established here can effectively predict the prognosis of glioma patients and provide a potential direction for immunotherapy.
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Mei Y, Zhao L, Jiang M, Yang F, Zhang X, Jia Y, Zhou N. Characterization of glucose metabolism in breast cancer to guide clinical therapy. Front Surg 2022; 9:973410. [PMID: 36277284 PMCID: PMC9580338 DOI: 10.3389/fsurg.2022.973410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
Background Breast cancer (BRCA) ranks as a leading cause of cancer death in women worldwide. Glucose metabolism is a noticeable characteristic of the occurrence of malignant tumors. In this study, we aimed to construct a novel glycometabolism-related gene (GRG) signature to predict overall survival (OS), immune infiltration and therapeutic response in BRCA patients. Materials and methods The mRNA sequencing and corresponding clinical data of BRCA patients were obtained from public cohorts. Lasso regression was applied to establish a GRG signature. The immune infiltration was evaluated with the ESTIMATE and CIBERSORT algorithms. The drug sensitivity was estimated using the value of IC50, and further forecasted the therapeutic response of each patient. The candidate target was selected in Cytoscape. A nomogram was constructed via the R package of “rms”. Results We constructed a six-GRG signature based on CACNA1H, CHPF, IRS2, NT5E, SDC1 and ATP6AP1, and the high-risk patients were correlated with poorer OS (P = 2.515 × 10−7). M2 macrophage infiltration was considerably superior in high-risk patients, and CD8+ T cell infiltration was significantly higher in low-risk patients. Additionally, the high-risk group was more sensitive to Lapatinib. Fortunately, SDC1 was recognized as candidate target and patients had a better OS in the low-SDC1 group. A nomogram integrating the GRG signature was developed, and calibration curves were consistent between the actual and predicted OS. Conclusions We identified a novel GRG signature complementing the present understanding of the targeted therapy and immune biomarker in breast cancer. The GRGs may provide fresh insights for individualized management of BRCA patients.
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Affiliation(s)
- Yingying Mei
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Lantao Zhao
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Man Jiang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Fangfang Yang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Xiaochun Zhang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Yizhen Jia
- Core Laboratory, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Correspondence: Na Zhou Yizhen Jia
| | - Na Zhou
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- Correspondence: Na Zhou Yizhen Jia
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31
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Zhang Y, Gao X, Bai X, Yao S, Chang YZ, Gao G. The emerging role of furin in neurodegenerative and neuropsychiatric diseases. Transl Neurodegener 2022; 11:39. [PMID: 35996194 PMCID: PMC9395820 DOI: 10.1186/s40035-022-00313-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 08/10/2022] [Indexed: 12/02/2022] Open
Abstract
Furin is an important mammalian proprotein convertase that catalyzes the proteolytic maturation of a variety of prohormones and proproteins in the secretory pathway. In the brain, the substrates of furin include the proproteins of growth factors, receptors and enzymes. Emerging evidence, such as reduced FURIN mRNA expression in the brains of Alzheimer's disease patients or schizophrenia patients, has implicated a crucial role of furin in the pathophysiology of neurodegenerative and neuropsychiatric diseases. Currently, compared to cancer and infectious diseases, the aberrant expression of furin and its pharmaceutical potentials in neurological diseases remain poorly understood. In this article, we provide an overview on the physiological roles of furin and its substrates in the brain, summarize the deregulation of furin expression and its effects in neurodegenerative and neuropsychiatric disorders, and discuss the implications and current approaches that target furin for therapeutic interventions. This review may expedite future studies to clarify the molecular mechanisms of furin deregulation and involvement in the pathogenesis of neurodegenerative and neuropsychiatric diseases, and to develop new diagnosis and treatment strategies for these diseases.
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Affiliation(s)
- Yi Zhang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China
| | - Xiaoqin Gao
- Shijiazhuang People's Hospital, Hebei Medical University, Shijiazhuang, 050027, China
| | - Xue Bai
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China
| | - Shanshan Yao
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China
| | - Yan-Zhong Chang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China.
| | - Guofen Gao
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China.
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32
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Fekrvand S, Khanmohammadi S, Abolhassani H, Yazdani R. B- and T-Cell Subset Abnormalities in Monogenic Common Variable Immunodeficiency. Front Immunol 2022; 13:912826. [PMID: 35784324 PMCID: PMC9241517 DOI: 10.3389/fimmu.2022.912826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/12/2022] [Indexed: 11/13/2022] Open
Abstract
Common variable immunodeficiency (CVID) is a heterogeneous group of inborn errors of immunity characterized by reduced serum concentrations of different immunoglobulin isotypes. CVID is the most prevalent symptomatic antibody deficiency with a broad range of infectious and non-infectious clinical manifestations. Various genetic and immunological defects are known to be involved in the pathogenesis of CVID. Monogenic defects account for the pathogenesis of about 20-50% of CVID patients, while a variety of cases do not have a defined genetic background. Deficiencies in molecules of B cell receptor signaling or other pathways involving B-cell development, activation, and proliferation could be associated with monogenetic defects of CVID. Genetic defects damping different B cell developmental stages can alter B- and even other lymphocytes’ differentiation and might be involved in the clinical and immunologic presentations of the disorder. Reports concerning T and B cell abnormalities have been published in CVID patients, but such comprehensive data on monogenic CVID patients is few and no review article exists to describe the abrogation of lymphocyte subsets in these disorders. Hence, we aimed to review the role of altered B- and T-cell differentiation in the pathogenesis of CVID patients with monogenic defects.
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Affiliation(s)
- Saba Fekrvand
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Science, Tehran, Iran
| | - Shaghayegh Khanmohammadi
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Science, Tehran, Iran
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Science, Tehran, Iran
- Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Reza Yazdani
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Science, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA, United States
- *Correspondence: Reza Yazdani, ;
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Barua S, Berger S, Pereira EM, Jobanputra V. Expanding the phenotype of ATP6AP1 deficiency. Cold Spring Harb Mol Case Stud 2022; 8:mcs.a006195. [PMID: 35732497 PMCID: PMC9235842 DOI: 10.1101/mcs.a006195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 04/08/2022] [Indexed: 11/24/2022] Open
Abstract
Vacuolar ATPases (V-ATPases) are large multisubunit proton pumps conserved among all eukaryotic cells that are involved in diverse functions including acidification of membrane-bound intracellular compartments. The ATP6AP1 gene encodes an accessory subunit of the vacuolar (V)-ATPase protein pump. Pathogenic variants in ATP6AP1 have been described in association with a congenital disorder of glycosylation (CDG), which are highly variable, but often characterized by immunodeficiency, hepatopathy, and neurologic manifestations. Although the most striking and common clinical feature is hepatopathy, the phenotypic and genotypic spectrum of ATP6AP1-CDG continues to expand. Here, we report identical twins who presented with acute liver failure and jaundice. Prenatal features included cystic hygroma, atrial septal defect, and ventriculomegaly. Postnatal features included pectus carinatum, connective tissue abnormalities, and hypospadias. Whole-exome sequencing (WES) revealed a novel de novo in-frame deletion in the ATP6AP1 gene (c.230_232delACT;p.Tyr77del). Although both twins have the commonly reported clinical feature of hepatopathy seen in other individuals with ATP6AP1-CDG-related disorder, they do not have neurological sequelae. This report expands the phenotypic spectrum of ATP6AP1-CDG-related disorder with both probands exhibiting unique prenatal and postnatal features, including fetal ventriculomegaly, umbilical hernia, pectus carinatum, micropenis, and hypospadias. Furthermore, this case affirms that neurological features described in the initial case series on ATP6AP1-CDG do not appear to be central, whereas the prenatal and connective tissue manifestations may be more common than previously thought. This emphasizes the importance of long-term clinical follow-up and variant interpretation using current updated recommendations.
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Affiliation(s)
- Subit Barua
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York 10032, USA
| | - Sara Berger
- Division of Clinical Genetics, Department of Pediatrics, Columbia University, Vagelos College of Physicians and Surgeons, New York, New York 10032, USA
| | - Elaine M Pereira
- Division of Clinical Genetics, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian Morgan Stanley Children's Hospital, New York, New York 10032, USA
| | - Vaidehi Jobanputra
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York 10032, USA
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Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment. Cell Death Dis 2022; 13:406. [PMID: 35468877 PMCID: PMC9039072 DOI: 10.1038/s41419-022-04858-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 11/16/2022]
Abstract
Alzheimer’s disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.
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Linders PTA, Ioannidis M, ter Beest M, van den Bogaart G. Fluorescence Lifetime Imaging of pH along the Secretory Pathway. ACS Chem Biol 2022; 17:240-251. [PMID: 35000377 PMCID: PMC8787756 DOI: 10.1021/acschembio.1c00907] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
![]()
Many cellular processes
are dependent on correct pH levels, and
this is especially important for the secretory pathway. Defects in
pH homeostasis in distinct organelles cause a wide range of diseases,
including disorders of glycosylation and lysosomal storage diseases.
Ratiometric imaging of the pH-sensitive mutant of green fluorescent
protein, pHLuorin, has allowed for targeted pH measurements in various
organelles, but the required sequential image acquisition is intrinsically
slow and therefore the temporal resolution is unsuitable to follow
the rapid transit of cargo between organelles. Therefore, we applied
fluorescence lifetime imaging microscopy (FLIM) to measure intraorganellar
pH with just a single excitation wavelength. We first validated this
method by confirming the pH in multiple compartments along the secretory
pathway and compared the pH values obtained by the FLIM-based measurements
with those obtained by conventional ratiometric imaging. Then, we
analyzed the dynamic pH changes within cells treated with Bafilomycin
A1, to block the vesicular ATPase, and Brefeldin A, to block endoplasmic
reticulum (ER)–Golgi trafficking. Finally, we followed the
pH changes of newly synthesized molecules of the inflammatory cytokine
tumor necrosis factor-α while they were in transit from the
ER via the Golgi to the plasma membrane. The toolbox we present here
can be applied to measure intracellular pH with high spatial and temporal
resolution and can be used to assess organellar pH in disease models.
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Affiliation(s)
- Peter T. A. Linders
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Melina Ioannidis
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747AG Groningen, Netherlands
| | - Martin ter Beest
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Geert van den Bogaart
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747AG Groningen, Netherlands
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Redmond MT, Scherzer R, Prince BT. Novel Genetic Discoveries in Primary Immunodeficiency Disorders. Clin Rev Allergy Immunol 2022; 63:55-74. [PMID: 35020168 PMCID: PMC8753955 DOI: 10.1007/s12016-021-08881-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2021] [Indexed: 01/12/2023]
Abstract
The field of Immunology is one that has undergone great expansion in recent years. With the advent of new diagnostic modalities including a variety of genetic tests (discussed elsewhere in this journal), the ability to diagnose a patient with a primary immunodeficiency disorder (PIDD) has become a more streamlined process. With increased availability of genetic testing for those with suspected or known PIDD, there has been a significant increase in the number of genes associated with this group of disorders. This is of great importance as a misdiagnosis of these rare diseases can lead to a delay in what can be critical treatment options. At times, those options can include life-saving medications or procedures. Presentation of patients with PIDD can vary greatly based on the specific genetic defect and the part(s) of the immune system that is affected by the variation. PIDD disorders lead to varying levels of increased risk of infection ranging from a mild increase such as with selective IgA deficiency to a profound risk with severe combined immunodeficiency. These diseases can also cause a variety of other clinical findings including autoimmunity and gastrointestinal disease.
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Affiliation(s)
- Margaret T. Redmond
- Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH USA
| | - Rebecca Scherzer
- Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH USA
| | - Benjamin T. Prince
- Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH USA
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Lougaris V, Plebani A. Predominantly Antibody Deficiencies. ENCYCLOPEDIA OF INFECTION AND IMMUNITY 2022:482-496. [DOI: 10.1016/b978-0-12-818731-9.00097-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Kim H, Han Y, Kim J, Lee M. RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes. Hepatol Commun 2021; 5:2121-2138. [PMID: 34558854 PMCID: PMC8631090 DOI: 10.1002/hep4.1785] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/25/2021] [Accepted: 06/24/2021] [Indexed: 12/30/2022] Open
Abstract
Lysosomes are intracellular acidic organelles with catabolic functions that contribute to the activation of autophagy. Although autophagy abnormality is associated with defects in lysosomal acidification during the progression of nonalcoholic fatty liver disease (NAFLD), the mechanisms of control of lysosomal acidification are not well understood at the molecular level. Thus, we aimed to elucidate the role of the orphan nuclear receptor retinoic acid-related orphan receptor α (RORα) in lysosomal acidification and autophagic flux, particularly in nutrition-enriched hepatocytes. First, lysosomal acidity was much lower in the hepatocytes obtained from hepatocyte-specific RORα-deleted (RORα-LKO) mice, whereas the infusion of an adenovirus encoding RORα in wild-type hepatocytes increased lysosomal acidity, as determined by LysoSensor. Second, the lysosomal translocation of the mechanistic target of rapamycin was increased and immature cathepsin D was accumulated in the liver of RORα-LKO mice. Third, the accumulation of LC3-II, p62/sequestosome 1 (SQSTM1), and neighbor of BRCA1 gene 1 (NBR1) was increased in the livers of RORα-LKO mice, indicating an impaired autophagic flux in the livers. Consistently, the number of autolysosomes containing mitochondria and lipid droplets was dramatically reduced in the RORα-deleted hepatocytes. Finally, we found that RORα induced the transcription of genes involved in lysosomal function, such as Atp6v1g1, a vacuolar H+ -ATPase (v-ATPase) subunit, which were largely down-regulated in the livers of mice with high-fat diet-induced NAFLD and patients with hepatitis. Conclusion: Targeting RORα may be a potential therapeutic strategy to restore lysosomal acidification, which inhibits the progression of NAFLD.
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Affiliation(s)
- Hyeon‐Ji Kim
- College of PharmacySeoul National UniversitySeoulKorea
| | - Yong‐Hyun Han
- Laboratory of Pathology and PhysiologyCollege of PharmacyKangwon National UniversityChuncheonSouth Korea
| | - Ju‐Yeon Kim
- College of PharmacySeoul National UniversitySeoulKorea
| | - Mi‐Ock Lee
- College of PharmacySeoul National UniversitySeoulKorea
- Bio‐MAX InstituteSeoul National UniversitySeoulKorea
- Research Institute of Pharmaceutical SciencesSeoulKorea
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39
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Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5. Nat Commun 2021; 12:6227. [PMID: 34711829 PMCID: PMC8553859 DOI: 10.1038/s41467-021-26534-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 10/05/2021] [Indexed: 12/26/2022] Open
Abstract
The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking. Measurements of cognate binding SNAREs, based on biotin-synchronizable forms of Stx5 (the RUSH system) and Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. Alternative starting codons of Stx5 are thus linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking.
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40
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A Novel Neuron-Specific Regulator of the V-ATPase in Drosophila. eNeuro 2021; 8:ENEURO.0193-21.2021. [PMID: 34620624 PMCID: PMC8541823 DOI: 10.1523/eneuro.0193-21.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 08/24/2021] [Accepted: 09/30/2021] [Indexed: 12/15/2022] Open
Abstract
The V-ATPase is a highly conserved enzymatic complex that ensures appropriate levels of organelle acidification in virtually all eukaryotic cells. While the general mechanisms of this proton pump have been well studied, little is known about the specific regulations of neuronal V-ATPase. Here, we studied CG31030, a previously uncharacterized Drosophila protein predicted from its sequence homology to be part of the V-ATPase family. In contrast to its ortholog ATP6AP1/VhaAC45 which is ubiquitous, we observed that CG31030 expression is apparently restricted to all neurons, and using CRISPR/Cas9-mediated gene tagging, that it is mainly addressed to synaptic terminals. In addition, we observed that CG31030 is essential for fly survival and that this protein co-immunoprecipitates with identified V-ATPase subunits, and in particular ATP6AP2. Using a genetically-encoded pH probe (VMAT-pHluorin) and electrophysiological recordings at the larval neuromuscular junction, we show that CG31030 knock-down induces a major defect in synaptic vesicle acidification and a decrease in quantal size, which is the amplitude of the postsynaptic response to the release of a single synaptic vesicle. These defects were associated with severe locomotor impairments. Overall, our data indicate that CG31030, which we renamed VhaAC45-related protein (VhaAC45RP), is a specific regulator of neuronal V-ATPase in Drosophila that is required for proper synaptic vesicle acidification and neurotransmitter release.
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41
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Larsen LE, van den Boogert MAW, Rios-Ocampo WA, Jansen JC, Conlon D, Chong PLE, Levels JHM, Eilers RE, Sachdev VV, Zelcer N, Raabe T, He M, Hand NJ, Drenth JPH, Rader DJ, Stroes ESG, Lefeber DJ, Jonker JW, Holleboom AG. Defective Lipid Droplet-Lysosome Interaction Causes Fatty Liver Disease as Evidenced by Human Mutations in TMEM199 and CCDC115. Cell Mol Gastroenterol Hepatol 2021; 13:583-597. [PMID: 34626841 PMCID: PMC8688563 DOI: 10.1016/j.jcmgh.2021.09.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/17/2021] [Accepted: 09/17/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS Recently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model. METHODS AND RESULTS Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity. CONCLUSIONS Our data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease.
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Affiliation(s)
- Lars E Larsen
- Department of Vascular Medicine, Amsterdam UMC, location AMC, Amsterdam, The Netherlands; Department of Pediatrics, Section Molecular Metabolism and Nutrition, University Medical Center Groningen, University of Groningen, The Netherlands
| | | | - Wilson A Rios-Ocampo
- Department of Pediatrics, Section Molecular Metabolism and Nutrition, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Jos C Jansen
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Donna Conlon
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Patrick L E Chong
- Department of Vascular Medicine, Amsterdam UMC, location AMC, Amsterdam, The Netherlands
| | - J Han M Levels
- Department of Vascular Medicine, Amsterdam UMC, location AMC, Amsterdam, The Netherlands
| | - Roos E Eilers
- Department of Pediatrics, Section Molecular Metabolism and Nutrition, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Vinay V Sachdev
- Department of Medical Biochemistry, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands
| | - Noam Zelcer
- Department of Medical Biochemistry, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands
| | - Tobias Raabe
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Miao He
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Division of Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Nicholas J Hand
- Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - David J Rader
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Division of Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Eric S G Stroes
- Department of Vascular Medicine, Amsterdam UMC, location AMC, Amsterdam, The Netherlands
| | - Dirk J Lefeber
- Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Johan W Jonker
- Department of Pediatrics, Section Molecular Metabolism and Nutrition, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Adriaan G Holleboom
- Department of Vascular Medicine, Amsterdam UMC, location AMC, Amsterdam, The Netherlands.
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42
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Liver Involvement in Congenital Disorders of Glycosylation: A Systematic Review. J Pediatr Gastroenterol Nutr 2021; 73:444-454. [PMID: 34173795 PMCID: PMC9255677 DOI: 10.1097/mpg.0000000000003209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
An ever-increasing number of disturbances in glycosylation have been described to underlie certain unexplained liver diseases presenting either almost isolated or in a multi-organ context. We aimed to update previous literature screenings which had identified up to 23 forms of congenital disorders of glycosylation (CDG) with associated liver disease. We conducted a comprehensive literature search of three scientific electronic databases looking at articles published during the last 20 years (January 2000-October 2020). Eligible studies were case reports/series reporting liver involvement in CDG patients. Our systematic review led us to point out 41 forms of CDG where the liver is primarily affected (n = 7) or variably involved in a multisystem disease with mandatory neurological abnormalities (n = 34). Herein we summarize individual clinical and laboratory presentation characteristics of these 41 CDG and outline their main presentation and diagnostic cornerstones with the aid of two synoptic tables. Dietary supplementation strategies have hitherto been investigated only in seven of these CDG types with liver disease, with a wide range of results. In conclusion, the systematic review recognized a liver involvement in a somewhat larger number of CDG variants corresponding to about 30% of the total of CDG so far reported, and it is likely that the number may increase further. This information could assist in an earlier correct diagnosis and a possibly proper management of these disorders.
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Johnsen C, Edmondson AC. Manifestations and Management of Hepatic Dysfunction in Congenital Disorders of Glycosylation. Clin Liver Dis (Hoboken) 2021; 18:54-66. [PMID: 34584669 PMCID: PMC8450475 DOI: 10.1002/cld.1105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 02/21/2021] [Indexed: 02/04/2023] Open
Affiliation(s)
| | - Andrew C. Edmondson
- Division of Human GeneticsDepartment of PediatricsChildren’s Hospital of PhiladelphiaPhiladelphiaPA
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44
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Yang X, Lv ZL, Tang Q, Chen XQ, Huang L, Yang MX, Lan LC, Shan QW. Congenital disorder of glycosylation caused by mutation of ATP6AP1 gene (c.1036G>A) in a Chinese infant: A case report. World J Clin Cases 2021; 9:7876-7885. [PMID: 34621841 PMCID: PMC8462236 DOI: 10.12998/wjcc.v9.i26.7876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/04/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The ATP6AP1 gene coding for the accessory protein Ac45 of the vacuolar-type adenosine triphosphatases (V-ATPase) is located on chromosome Xq28. Defects in certain subunits or accessory subunits of the V-ATPase can lead to congenital disorders of glycosylation (CDG). CDG is a group of metabolic disorders in which defective protein and lipid glycosylation processes affect multiple tissues and organs. Therefore, the clinical presentation of patients with ATP6AP1-CDG varies widely. In this report, we present a case of ATP6AP1-CDG in a Chinese infant, with clinical features and genotype.
CASE SUMMARY An 8-mo-old boy was admitted to our hospital because unexplained hepatosplenomegaly and elevated transaminases that had been noted while he was being treated for a cough at a local hospital. A post-admission examination at our hospital revealed abnormalities in the infant’s liver, brain, and immune system. Trio-based whole exome gene analysis identified a hemizygous pathogenic mutation c.1036G>A (p.E346K) in exon 9 of the ATP6AP1 gene. This variant of the ATP6AP1 gene has not been reported in East Asian countries until now.
CONCLUSION Based on the infant’s clinical manifestations and the results of genetic detection, he was clearly diagnosed with ATP6AP1-CDG. The clinical manifestations of children with CDG vary widely. Genetic testing analysis helps in the clinical diagnosis of children with CDG.
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Affiliation(s)
- Xia Yang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zi-Li Lv
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Qing Tang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiu-Qi Chen
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Li Huang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Mei-Xiong Yang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Lian-Cheng Lan
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Qing-Wen Shan
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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45
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Wang J, Liu Y, Zhang S. Prognostic and immunological value of ATP6AP1 in breast cancer: implications for SARS-CoV-2. Aging (Albany NY) 2021; 13:16904-16921. [PMID: 34228637 PMCID: PMC8312471 DOI: 10.18632/aging.203229] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 05/11/2021] [Indexed: 12/24/2022]
Abstract
Abnormal ATPase H+ Transporting Accessory Protein 1 (ATP6AP1) expression may promote carcinogenesis. We investigated the association of ATP6AP1 with breast cancer (BC) and COVID-19. The Oncomine, Gene Expression Profiling Interactive Analysis, Human Protein Atlas and Kaplan-Meier plotter databases were used to evaluate the expression and prognostic value of ATP6AP1 in BC. ATP6AP1 was upregulated in BC tissues, and higher ATP6AP1 expression was associated with poorer outcomes. Data from the Tumor Immune Estimation Resource, Tumor-Immune System Interaction Database and Kaplan-Meier plotter indicated that ATP6AP1 expression correlated with immune infiltration, and that its prognostic effects in BC depended on tumor-infiltrating immune cell subtype levels. Multiple databases were used to evaluate the association of ATP6AP1 with clinicopathological factors, assess the mutation and methylation of ATP6AP1, and analyze gene co-expression and enrichment. The ATP6AP1 promoter was hypomethylated in BC tissues and differentially methylated between different disease stages and subtypes. Data from the Gene Expression Omnibus indicated that ATP6AP1 levels in certain cell types were reduced after SARS-CoV-2 infections. Ultimately, higher ATP6AP1 expression was associated with a poorer prognosis and with higher or lower infiltration of particular immune cells in BC. BC patients may be particularly susceptible to SARS-CoV-2 infections, which may alter their prognoses.
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Affiliation(s)
- Jintian Wang
- Department of Breast Surgery, The Fourth Hospital of Hebei Medical University, Hebei, Shijiazhuang 050011, China
| | - Yunjiang Liu
- Department of Breast Surgery, The Fourth Hospital of Hebei Medical University, Hebei, Shijiazhuang 050011, China
| | - Shuo Zhang
- Department of Breast Surgery, The Fourth Hospital of Hebei Medical University, Hebei, Shijiazhuang 050011, China
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46
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Harvey DJ. ANALYSIS OF CARBOHYDRATES AND GLYCOCONJUGATES BY MATRIX-ASSISTED LASER DESORPTION/IONIZATION MASS SPECTROMETRY: AN UPDATE FOR 2015-2016. MASS SPECTROMETRY REVIEWS 2021; 40:408-565. [PMID: 33725404 DOI: 10.1002/mas.21651] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/24/2020] [Indexed: 06/12/2023]
Abstract
This review is the ninth update of the original article published in 1999 on the application of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2016. Also included are papers that describe methods appropriate to analysis by MALDI, such as sample preparation techniques, even though the ionization method is not MALDI. Topics covered in the first part of the review include general aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, fragmentation and arrays. The second part of the review is devoted to applications to various structural types such as oligo- and poly-saccharides, glycoproteins, glycolipids, glycosides and biopharmaceuticals. Much of this material is presented in tabular form. The third part of the review covers medical and industrial applications of the technique, studies of enzyme reactions and applications to chemical synthesis. The reported work shows increasing use of combined new techniques such as ion mobility and the enormous impact that MALDI imaging is having. MALDI, although invented over 30 years ago is still an ideal technique for carbohydrate analysis and advancements in the technique and range of applications show no sign of deminishing. © 2020 Wiley Periodicals, Inc.
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Affiliation(s)
- David J Harvey
- Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Roosevelt Drive, Oxford, OX3 7FZ, United Kingdom
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47
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Santra P, Amack JD. Loss of vacuolar-type H+-ATPase induces caspase-independent necrosis-like death of hair cells in zebrafish neuromasts. Dis Model Mech 2021; 14:dmm048997. [PMID: 34296747 PMCID: PMC8319552 DOI: 10.1242/dmm.048997] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 06/15/2021] [Indexed: 01/24/2023] Open
Abstract
The vacuolar-type H+-ATPase (V-ATPase) is a multi-subunit proton pump that regulates cellular pH. V-ATPase activity modulates several cellular processes, but cell-type-specific functions remain poorly understood. Patients with mutations in specific V-ATPase subunits can develop sensorineural deafness, but the underlying mechanisms are unclear. Here, we show that V-ATPase mutations disrupt the formation of zebrafish neuromasts, which serve as a model to investigate hearing loss. V-ATPase mutant neuromasts are small and contain pyknotic nuclei that denote dying cells. Molecular markers and live imaging show that loss of V-ATPase induces mechanosensory hair cells in neuromasts, but not neighboring support cells, to undergo caspase-independent necrosis-like cell death. This is the first demonstration that loss of V-ATPase can lead to necrosis-like cell death in a specific cell type in vivo. Mechanistically, loss of V-ATPase reduces mitochondrial membrane potential in hair cells. Modulating the mitochondrial permeability transition pore, which regulates mitochondrial membrane potential, improves hair cell survival. These results have implications for understanding the causes of sensorineural deafness, and more broadly, reveal functions for V-ATPase in promoting survival of a specific cell type in vivo.
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Affiliation(s)
- Peu Santra
- Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA
| | - Jeffrey D. Amack
- Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA
- BioInspired Syracuse: Institute for Material and Living Systems, Syracuse, NY 13244, USA
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48
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Pottie L, Van Gool W, Vanhooydonck M, Hanisch FG, Goeminne G, Rajkovic A, Coucke P, Sips P, Callewaert B. Loss of zebrafish atp6v1e1b, encoding a subunit of vacuolar ATPase, recapitulates human ARCL type 2C syndrome and identifies multiple pathobiological signatures. PLoS Genet 2021; 17:e1009603. [PMID: 34143769 PMCID: PMC8244898 DOI: 10.1371/journal.pgen.1009603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 06/30/2021] [Accepted: 05/17/2021] [Indexed: 11/27/2022] Open
Abstract
The inability to maintain a strictly regulated endo(lyso)somal acidic pH through the proton-pumping action of the vacuolar-ATPases (v-ATPases) has been associated with various human diseases including heritable connective tissue disorders. Autosomal recessive (AR) cutis laxa (CL) type 2C syndrome is associated with genetic defects in the ATP6V1E1 gene and is characterized by skin wrinkles or loose redundant skin folds with pleiotropic systemic manifestations. The underlying pathological mechanisms leading to the clinical presentations remain largely unknown. Here, we show that loss of atp6v1e1b in zebrafish leads to early mortality, associated with craniofacial dysmorphisms, vascular anomalies, cardiac dysfunction, N-glycosylation defects, hypotonia, and epidermal structural defects. These features are reminiscent of the phenotypic manifestations in ARCL type 2C patients. Our data demonstrates that loss of atp6v1e1b alters endo(lyso)somal protein levels, and interferes with non-canonical v-ATPase pathways in vivo. In order to gain further insights into the processes affected by loss of atp6v1e1b, we performed an untargeted analysis of the transcriptome, metabolome, and lipidome in early atp6v1e1b-deficient larvae. We report multiple affected pathways including but not limited to oxidative phosphorylation, sphingolipid, fatty acid, and energy metabolism together with profound defects on mitochondrial respiration. Taken together, our results identify complex pathobiological effects due to loss of atp6v1e1b in vivo. Cutis laxa syndromes are pleiotropic disorders of the connective tissue, characterized by skin redundancy and variable systemic manifestations. Cutis laxa syndromes are caused by pathogenic variants in genes encoding structural and regulatory components of the extracellular matrix or in genes encoding components of cellular trafficking, metabolism, and mitochondrial function. Pathogenic variants in genes coding for vacuolar-ATPases, a multisubunit complex responsible for the acidification of multiple intracellular vesicles, cause type 2 cutis laxa syndromes, a group of cutis laxa subtypes further characterized by neurological, skeletal, and rarely cardiopulmonary manifestations. To investigate the pathomechanisms of vacuolar-ATPase dysfunction, we generated zebrafish models that lack a crucial subunit of the vacuolar-ATPases. The mutant zebrafish models show morphological and functional features reminiscent of the phenotypic manifestations in cutis laxa patients carrying pathogenic variants in ATP6V1E1. In-depth analysis at multiple -omic levels identified biological signatures that indicate impairment of signaling pathways, lipid metabolism, and mitochondrial respiration. We anticipate that these data will contribute to a better understanding of the pathogenesis of cutis laxa syndromes and other disorders involving defective v-ATPase function, which may eventually improve patient treatment and management.
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Affiliation(s)
- Lore Pottie
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Wouter Van Gool
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Michiel Vanhooydonck
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Franz-Georg Hanisch
- Institute of Biochemistry II, Medical Faculty, University of Cologne, Cologne, Germany
| | - Geert Goeminne
- VIB Metabolomics Core Ghent, Ghent, Belgium
- Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent, Belgium
| | - Andreja Rajkovic
- Department of Food technology, Safety and Health, Faculty of Bioscience Engineering, University of Ghent, Ghent, Belgium
| | - Paul Coucke
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Patrick Sips
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Bert Callewaert
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- * E-mail:
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A mutation in SLC37A4 causes a dominantly inherited congenital disorder of glycosylation characterized by liver dysfunction. Am J Hum Genet 2021; 108:1040-1052. [PMID: 33964207 DOI: 10.1016/j.ajhg.2021.04.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/20/2021] [Indexed: 02/08/2023] Open
Abstract
SLC37A4 encodes an endoplasmic reticulum (ER)-localized multitransmembrane protein required for transporting glucose-6-phosphate (Glc-6P) into the ER. Once transported into the ER, Glc-6P is subsequently hydrolyzed by tissue-specific phosphatases to glucose and inorganic phosphate during times of glucose depletion. Pathogenic variants in SLC37A4 cause an established recessive disorder known as glycogen storage disorder 1b characterized by liver and kidney dysfunction with neutropenia. We report seven individuals who presented with liver dysfunction multifactorial coagulation deficiency and cardiac issues and were heterozygous for the same variant, c.1267C>T (p.Arg423∗), in SLC37A4; the affected individuals were from four unrelated families. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans, while N-glycans in fibroblasts and undifferentiated iPSC were normal. Due to the liver-specific nature of this disorder, we generated a CRISPR base-edited hepatoma cell line harboring the c.1267C>T (p.Arg423∗) variant. These cells replicated the secreted abnormalities seen in serum N-glycosylation, and a portion of the mutant protein appears to relocate to a distinct, non-Golgi compartment, possibly ER exit sites. These cells also show a gene dosage-dependent alteration in the Golgi morphology and reduced intraluminal pH that may account for the altered glycosylation. In summary, we identify a recurrent mutation in SLC37A4 that causes a dominantly inherited congenital disorder of glycosylation characterized by coagulopathy and liver dysfunction with abnormal serum N-glycans.
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Zhu X, Zhang H, Mendell JT. Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3' UTR-Directed Regulation and Nonsense-Mediated Decay. Cell Rep 2021; 32:107895. [PMID: 32668236 PMCID: PMC7433747 DOI: 10.1016/j.celrep.2020.107895] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 06/09/2020] [Accepted: 06/22/2020] [Indexed: 12/26/2022] Open
Abstract
Nonsense-mediated decay (NMD) is a pathway that degrades mRNAs containing premature termination codons. Here we describe a genome-wide screen for NMD factors that uncovers an unexpected mechanism that broadly governs 3' untranslated region (UTR)-directed regulation. The screen reveals that NMD requires lysosomal acidification, which allows transferrin-mediated iron uptake, which, in turn, is necessary for iron-sulfur (Fe-S) cluster biogenesis. This pathway maintains the activity of the Fe-S cluster-containing ribosome recycling factor ABCE1, whose impaired function results in movement of ribosomes into 3' UTRs, where they displace exon junction complexes, abrogating NMD. Importantly, these effects extend beyond NMD substrates, with ABCE1 activity required to maintain the accessibility of 3' UTRs to diverse regulators, including microRNAs and RNA binding proteins. Because of the sensitivity of the Fe-S cluster of ABCE1 to iron availability and reactive oxygen species, these findings reveal an unanticipated vulnerability of 3' UTR-directed regulation to lysosomal dysfunction, iron deficiency, and oxidative stress.
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Affiliation(s)
- Xiaoqiang Zhu
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
| | - He Zhang
- Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Joshua T Mendell
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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