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1
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Gazeu A, Collardeau-Frachon S. Practical Approach to Congenital Anomalies of the Kidneys: Focus on Anomalies With Insufficient or Abnormal Nephron Development: Renal Dysplasia, Renal Hypoplasia, and Renal Tubular Dysgenesis. Pediatr Dev Pathol 2024; 27:459-493. [PMID: 39270126 DOI: 10.1177/10935266241239241] [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] [Indexed: 09/15/2024]
Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) accounts for up to 30% of antenatal congenital anomalies and is the main cause of kidney failure in children worldwide. This review focuses on practical approaches to CAKUT, particularly those with insufficient or abnormal nephron development, such as renal dysplasia, renal hypoplasia, and renal tubular dysgenesis. The review provides insights into the histological features, pathogenesis, mechanisms, etiologies, antenatal and postnatal presentation, management, and prognosis of these anomalies. Differential diagnoses are discussed as several syndromes may include CAKUT as a phenotypic component and renal dysplasia may occur in some ciliopathies, tumor predisposition syndromes, and inborn errors of metabolism. Diagnosis and genetic counseling for CAKUT are challenging, due to the extensive variability in presentation, genetic and phenotypic heterogeneity, and difficulties to assess postnatal lung and renal function on prenatal imaging. The review highlights the importance of perinatal autopsy and pathological findings in surgical specimens to establish the diagnosis and prognosis of CAKUT. The indications and the type of genetic testing are discussed. The aim is to provide essential insights into the practical approaches, diagnostic processes, and genetic considerations offering valuable guidance for pediatric and perinatal pathologists.
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Affiliation(s)
- Alexia Gazeu
- Department of pathology, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, University Hospital of Lyon, Lyon Bron, France
- Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France
| | - Sophie Collardeau-Frachon
- Department of pathology, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, University Hospital of Lyon, Lyon Bron, France
- Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France
- Société française de Fœtopathologie, Soffoet, Paris, France
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2
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Yang J, Xiao S, Li L, Zhu A, Xiao W, Wang Q. Actin Dysregulation Mediates Nephrotoxicity of Cassiae Semen Aqueous Extracts. TOXICS 2024; 12:556. [PMID: 39195658 PMCID: PMC11360101 DOI: 10.3390/toxics12080556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/05/2024] [Accepted: 07/26/2024] [Indexed: 08/29/2024]
Abstract
Cassiae semen, commonly consumed as roasted tea, has been widely used for both medicinal purposes and dietary supplements. In this study, we investigated the nephrotoxic effects and underlying mechanisms of Cassiae semen aqueous extracts (CSAEs) using computational and animal models. Both male and female Sprague Dawley rats were treated with 4.73-47.30 g/kg (body weight) of CSAEs by oral gavage twice a day for 7-28 days. We found that serum and urinary biomarkers of kidney injury and kidney coefficients were increased in a dose-dependent manner, and were accompanied by morphological alterations in the kidneys of CSAEs-treated rats. Computational and molecular docking approaches predicted that the three most abundant components of CSAEs-obtusifolin, aurantio-obtusin, and obtusin-exhibited strong affinity for the binding of F-actin, ROCK1, and Rac1, and the RhoA-ROCK pathway was identified as the most likely regulatory mechanism mediating the nephrotoxicity of CSAEs. Consistently, immunofluorescence staining revealed F-actin and cytoskeleton were frequently disturbed in renal cells and brush borders at high doses of CSAEs. Results from gene expression analyses confirmed that CSAEs suppressed the key proteins in the RhoA-ROCK signaling pathway and consequently the expression of F-actin and its stabilization genes. In summary, our findings suggest that Cassiae semen can depolymerize and destabilize actin cytoskeleton by inhibition of the RhoA-ROCK pathway and/or direct binding to F-actin, leading to nephrotoxicity. The consumption of Cassiae semen as a supplement and medicine warrants attention.
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Affiliation(s)
- Jinlan Yang
- Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China; (J.Y.); (S.X.); (L.L.); (A.Z.); (W.X.)
| | - Sheng Xiao
- Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China; (J.Y.); (S.X.); (L.L.); (A.Z.); (W.X.)
| | - Ludi Li
- Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China; (J.Y.); (S.X.); (L.L.); (A.Z.); (W.X.)
| | - An Zhu
- Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China; (J.Y.); (S.X.); (L.L.); (A.Z.); (W.X.)
| | - Wusheng Xiao
- Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China; (J.Y.); (S.X.); (L.L.); (A.Z.); (W.X.)
| | - Qi Wang
- Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China; (J.Y.); (S.X.); (L.L.); (A.Z.); (W.X.)
- Key Laboratory of State Administration of Traditional Chinese Medicine (TCM) for Compatibility Toxicology, Peking University, Beijing 100191, China
- Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Peking University, Beijing 100191, China
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Yuan X, Ma Y, Gao R, Cui S, Wang Y, Fa B, Ma S, Wei T, Ma S, Yu Z. HEARTSVG: a fast and accurate method for identifying spatially variable genes in large-scale spatial transcriptomics. Nat Commun 2024; 15:5700. [PMID: 38972896 PMCID: PMC11228050 DOI: 10.1038/s41467-024-49846-1] [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: 06/29/2023] [Accepted: 06/19/2024] [Indexed: 07/09/2024] Open
Abstract
Identifying spatially variable genes (SVGs) is crucial for understanding the spatiotemporal characteristics of diseases and tissue structures, posing a distinctive challenge in spatial transcriptomics research. We propose HEARTSVG, a distribution-free, test-based method for fast and accurately identifying spatially variable genes in large-scale spatial transcriptomic data. Extensive simulations demonstrate that HEARTSVG outperforms state-of-the-art methods with higherF 1 scores (averageF 1 Score=0.948), improved computational efficiency, scalability, and reduced false positives (FPs). Through analysis of twelve real datasets from various spatial transcriptomic technologies, HEARTSVG identifies a greater number of biologically significant SVGs (average AUC = 0.792) than other comparative methods without prespecifying spatial patterns. Furthermore, by clustering SVGs, we uncover two distinct tumor spatial domains characterized by unique spatial expression patterns, spatial-temporal locations, and biological functions in human colorectal cancer data, unraveling the complexity of tumors.
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Affiliation(s)
- Xin Yuan
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
- SJTU-Yale Joint Center for Biostatistics and Data Science Organization, Shanghai Jiao Tong University, Shanghai, China
| | - Yanran Ma
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Ruitian Gao
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Shuya Cui
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
- SJTU-Yale Joint Center for Biostatistics and Data Science Organization, Shanghai Jiao Tong University, Shanghai, China
| | - Yifan Wang
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Botao Fa
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Shiyang Ma
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting Wei
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Shuangge Ma
- SJTU-Yale Joint Center for Biostatistics and Data Science Organization, Shanghai Jiao Tong University, Shanghai, China.
- Department of Biostatistics, Yale University, New Haven, USA.
| | - Zhangsheng Yu
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
- SJTU-Yale Joint Center for Biostatistics and Data Science Organization, Shanghai Jiao Tong University, Shanghai, China.
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Center for Biomedical Data Science, Translational Science Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Devavarapu PKV, Uppaluri KR, Nikhade VA, Palasamudram K, Sri Manjari K. Exploring the complexities of megacystis-microcolon-intestinal hypoperistalsis syndrome: insights from genetic studies. Clin J Gastroenterol 2024; 17:383-395. [PMID: 38461165 DOI: 10.1007/s12328-024-01934-x] [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: 08/03/2023] [Accepted: 01/30/2024] [Indexed: 03/11/2024]
Abstract
Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is an uncommon genetic disorder inherited in an autosomal recessive pattern that affects the muscles that line the bladder and intestines. The most common genes associated with MMIHS mutations are ACTG2, LMOD1, MYH11, MYL9, MYLK, and PDCL3. However, the complete genetic landscape of MMIHS still needs to be fully understood. The diagnosis of MMIHS can be challenging. However, advances in prenatal and diagnostic techniques, such as ultrasound and fetal urine analysis, have improved the ability to detect the syndrome early. Targeted next-generation sequencing (NGS) and other diagnostic tests can also diagnose MMIHS. The management of MMIHS involves addressing severe intestinal dysmotility, which often necessitates total parenteral nutrition (TPN), which can lead to complications such as hepatotoxicity and nutritional deficiencies. Multivisceral and intestinal transplantation has emerged as therapeutic options, offering the potential for improved outcomes and enteral autonomy. Understanding the genetic underpinnings of MMIHS is crucial for personalized care. While the prognosis varies, timely interventions and careful monitoring enhance patient outcomes. Genetic studies have given us valuable insights into the molecular mechanisms of MMIHS. These studies have identified mutations in genes involved in the development and function of smooth muscle cells. They have also shown that MMIHS is associated with defects in the signaling pathways that control muscle contraction. Continued research in the genetics of MMIHS holds promise for unraveling the complexities of MMIHS and improving the lives of affected individuals.
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Affiliation(s)
- Prasad K V Devavarapu
- Department of Biochemistry, GITAM Institute of Medical Sciences & Research, Rushikonda, Visakhapatnam, Andhra Pradesh, 530045, India
| | - Kalyan Ram Uppaluri
- GenepoweRx, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana, 500033, India
| | - Vrushabh Anil Nikhade
- KIT's College of Engineering (Autonomous), Kolhapur, Maharashtra, 416234, India
- GenepoweRx, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana, 500033, India
| | - Kalyani Palasamudram
- GenepoweRx, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana, 500033, India
| | - Kavutharapu Sri Manjari
- GenepoweRx, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana, 500033, India.
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Ceron RH, Báez-Cruz FA, Palmer NJ, Carman PJ, Boczkowska M, Heuckeroth RO, Ostap EM, Dominguez R. Molecular mechanisms linking missense ACTG2 mutations to visceral myopathy. SCIENCE ADVANCES 2024; 10:eadn6615. [PMID: 38820162 PMCID: PMC11141634 DOI: 10.1126/sciadv.adn6615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 04/29/2024] [Indexed: 06/02/2024]
Abstract
Visceral myopathy is a life-threatening disease characterized by muscle weakness in the bowel, bladder, and uterus. Mutations in smooth muscle γ-actin (ACTG2) are the most common cause of the disease, but the mechanisms by which the mutations alter muscle function are unknown. Here, we examined four prevalent ACTG2 mutations (R40C, R148C, R178C, and R257C) that cause different disease severity and are spread throughout the actin fold. R178C displayed premature degradation, R148C disrupted interactions with actin-binding proteins, R40C inhibited polymerization, and R257C destabilized filaments. Because these mutations are heterozygous, we also analyzed 50/50 mixtures with wild-type (WT) ACTG2. The WT/R40C mixture impaired filament nucleation by leiomodin 1, and WT/R257C produced filaments that were easily fragmented by smooth muscle myosin. Smooth muscle tropomyosin isoform Tpm1.4 partially rescued the defects of R40C and R257C. Cryo-electron microscopy structures of filaments formed by R40C and R257C revealed disrupted intersubunit contacts. The biochemical and structural properties of the mutants correlate with their genotype-specific disease severity.
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Affiliation(s)
- Rachel H. Ceron
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- The Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA
| | - Faviolla A. Báez-Cruz
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas J. Palmer
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Peter J. Carman
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Malgorzata Boczkowska
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert O. Heuckeroth
- The Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - E. Michael Ostap
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Roberto Dominguez
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Billon C, Piccoli GB, de Sainte Agathe JM, Stoeva R, Derive N, Heidet L, Berrebi D, Bruneval P, Jeunemaitre X, Hureaux M. Genome-wide analysis identifies MYH11 compound heterozygous variants leading to visceral myopathy corresponding to late-onset form of megacystis-microcolon-intestinal hypoperistalsis syndrome. Mol Genet Genomics 2024; 299:44. [PMID: 38625590 DOI: 10.1007/s00438-024-02136-3] [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: 07/05/2023] [Accepted: 03/26/2024] [Indexed: 04/17/2024]
Abstract
Megacystis-microcolon-hypoperistalsis-syndrome (MMIHS) is a rare and early-onset congenital disease characterized by massive abdominal distension due to a large non-obstructive bladder, a microcolon and decreased or absent intestinal peristalsis. While in most cases inheritance is autosomal dominant and associated with heterozygous variant in ACTG2 gene, an autosomal recessive transmission has also been described including pathogenic bialellic loss-of-function variants in MYH11. We report here a novel family with visceral myopathy related to MYH11 gene, confirmed by whole genome sequencing (WGS). WGS was performed in two siblings with unusual presentation of MMIHS and their two healthy parents. The 38 years-old brother had severe bladder dysfunction and intestinal obstruction, whereas the 30 years-old sister suffered from end-stage kidney disease with neurogenic bladder and recurrent sigmoid volvulus. WGS was completed by retrospective digestive pathological analyses. Compound heterozygous variants of MYH11 gene were identified, associating a deletion of 1.2 Mb encompassing MYH11 inherited from the father and an in-frame variant c.2578_2580del, p.Glu860del inherited from the mother. Pathology analyses of the colon and the rectum revealed structural changes which significance of which is discussed. Cardiac and vascular assessment of the mother was normal. This is the second report of a visceral myopathy corresponding to late-onset form of MMIHS related to compound heterozygosity in MYH11; with complete gene deletion and a hypomorphic allele in trans. The hypomorphic allele harbored by the mother raised the question of the risk of aortic disease in adults. This case shows the interest of WGS in deciphering complex phenotypes, allowing adapted diagnosis and genetic counselling.
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Affiliation(s)
- Clarisse Billon
- Université Paris Cité, Paris, France
- Service de Médecine Génomique des Maladies Rares, Groupe Hospitalier Universitaire Centre, Assistance Publique Hôpitaux de Paris, 75015, Paris, France
| | | | - Jean-Madeleine de Sainte Agathe
- Laboratoire de Biologie Médicale MultiSites SeqOIA, Paris, France
- Département de Génétique Médicale, Groupe Hospitalier Universitaire Pitié Salpêtrière, Assistance Publique Hôpitaux de Paris, Sorbonne Université, Paris, France
| | - Radka Stoeva
- Service de Génétique Médicale, Centre Hospitalier du Mans, Le Mans, France
| | - Nicolas Derive
- Laboratoire de Biologie Médicale MultiSites SeqOIA, Paris, France
| | - Laurence Heidet
- Centre de référence des Maladies Rénales Héréditaires de L'Enfant Et de L'Adulte, MARHEA, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015, Paris, France
- Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015, Paris, France
| | - Dominique Berrebi
- Université Paris Cité, Paris, France
- Service de Pathologie, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015, Paris, France
| | - Patrick Bruneval
- Université Paris Cité, Paris, France
- Service de Cardiologie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, 75015, Paris, France
| | - Xavier Jeunemaitre
- Université Paris Cité, Paris, France
- Service de Médecine Génomique des Maladies Rares, Groupe Hospitalier Universitaire Centre, Assistance Publique Hôpitaux de Paris, 75015, Paris, France
| | - Marguerite Hureaux
- Université Paris Cité, Paris, France.
- Service de Médecine Génomique des Maladies Rares, Groupe Hospitalier Universitaire Centre, Assistance Publique Hôpitaux de Paris, 75015, Paris, France.
- Centre de référence des Maladies Rénales Héréditaires de L'Enfant Et de L'Adulte, MARHEA, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015, Paris, France.
- INSERM, PARCC U970, 75015, Paris, France.
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Wang L, Bu T, Wu X, Li L, Sun F, Cheng CY. Motor proteins, spermatogenesis and testis function. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 141:381-445. [PMID: 38960481 DOI: 10.1016/bs.apcsb.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/05/2024]
Abstract
The role of motor proteins in supporting intracellular transports of vesicles and organelles in mammalian cells has been known for decades. On the other hand, the function of motor proteins that support spermatogenesis is also well established since the deletion of motor protein genes leads to subfertility and/or infertility. Furthermore, mutations and genetic variations of motor protein genes affect fertility in men, but also a wide range of developmental defects in humans including multiple organs besides the testis. In this review, we seek to provide a summary of microtubule and actin-dependent motor proteins based on earlier and recent findings in the field. Since these two cytoskeletons are polarized structures, different motor proteins are being used to transport cargoes to different ends of these cytoskeletons. However, their involvement in germ cell transport across the blood-testis barrier (BTB) and the epithelium of the seminiferous tubules remains relatively unknown. It is based on recent findings in the field, we have provided a hypothetical model by which motor proteins are being used to support germ cell transport across the BTB and the seminiferous epithelium during the epithelial cycle of spermatogenesis. In our discussion, we have highlighted the areas of research that deserve attention to bridge the gap of research in relating the function of motor proteins to spermatogenesis.
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Affiliation(s)
- Lingling Wang
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China; Department of Urology and Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Tiao Bu
- Department of Urology and Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Xiaolong Wu
- Department of Urology and Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Linxi Li
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Fei Sun
- Department of Urology and Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - C Yan Cheng
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China; Department of Urology and Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
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Liu S, Zhao Y, Li S, Li Y, Liu L, Sheng J, Tian Y, Gao X. Network pharmacology combined with an animal model to reveal the material basis and mechanism of Amomum villosum in alleviating constipation in mice. Gene 2024; 897:148064. [PMID: 38065427 DOI: 10.1016/j.gene.2023.148064] [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: 10/13/2023] [Revised: 11/21/2023] [Accepted: 12/04/2023] [Indexed: 01/17/2024]
Abstract
Constipation is a prevalent gastrointestinal disorder, with its prevalence showing an annual upward trend. There are many factors involved in the occurrence of constipation, such as abnormal smooth muscle contraction and disorders of gastrointestinal hormone secretion. Amomum villosum (A. villosum) has been proven to be effective in improving digestive system diseases, but there is no report on improving constipation. Therefore, we used network pharmacology prediction combined with animal experiments to explore the key active components of A. villosum and their pharmacological mechanisms. The results of network pharmacological prediction showed that β-sitosterol was the key laxative compound of A. villosum, which may play a laxative role by activating the adrenoceptor alpha 1 A-myosin light chain (ADRA1A-MLC) pathway. Further animal experiments showed that β-sitosterol could significantly shorten the time to first black stool; increase faecal weight, faecal number, and faecal water content; and promote gastrointestinal motility. β-sitosterol may promote intestinal motility by upregulating the expression of ADRA1A and myosin light chain 9 (Myl9) mRNA and protein in the colon, thereby activating the ADRA1A-MLC signalling pathway. In addition, it is possible to improve constipation symptoms by regulating serum neurotransmitters and gastrointestinal motility-related factors, such as the serum content of 5-hydroxytryptamine (5-HT) and acetylcholinesterase (AchE) and the mRNA expression of 5-hydroxytryptamine receptor 4 (5-HT4), stem cell factor (SCF), stem cell factor receptor (c-Kit) and smooth muscle myosin light chain kinase (smMLCK) in the colon. These results lay a foundation for the application of A. villosum and β-sitosterol in constipation.
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Affiliation(s)
- Shuangfeng Liu
- Yunnan Key Laboratory of Precision Nutrition and Personalized Food Manufacturing, Yunnan Agricultural University, Kunming 650201, China; College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, China; Engineering Research Center of Development and Utilization of Food and Drug Homologous Resources, Ministry of Education, Yunnan Agricultural University, Kunming 650201, China
| | - Yan Zhao
- Division of Science and Technology, Yunnan Agricultural University, Kunming 650201, China
| | - Sijin Li
- College of Tea (Pu'er), West Yunnan University of Applied Sciences, Puer 665099, China
| | - Yanan Li
- College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, China
| | - Li Liu
- College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, China
| | - Jun Sheng
- Engineering Research Center of Development and Utilization of Food and Drug Homologous Resources, Ministry of Education, Yunnan Agricultural University, Kunming 650201, China
| | - Yang Tian
- Yunnan Key Laboratory of Precision Nutrition and Personalized Food Manufacturing, Yunnan Agricultural University, Kunming 650201, China; Engineering Research Center of Development and Utilization of Food and Drug Homologous Resources, Ministry of Education, Yunnan Agricultural University, Kunming 650201, China.
| | - Xiaoyu Gao
- Yunnan Key Laboratory of Precision Nutrition and Personalized Food Manufacturing, Yunnan Agricultural University, Kunming 650201, China; College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, China; Engineering Research Center of Development and Utilization of Food and Drug Homologous Resources, Ministry of Education, Yunnan Agricultural University, Kunming 650201, China.
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9
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Chen CP. Syndromic and single gene disorders associated with fetal megacystis (I): Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). Taiwan J Obstet Gynecol 2024; 63:19-21. [PMID: 38216263 DOI: 10.1016/j.tjog.2023.11.007] [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] [Accepted: 11/02/2023] [Indexed: 01/14/2024] Open
Abstract
Fetal megacystis has been reported to be associated with chromosomal abnormalities, megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), obstructive uropathy, prune belly syndrome, cloacal anomalies, limb-body wall complex, amniotic band syndrome, anorectal malformations, VACTERL association (vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula, renal anomalies and limb abnormalities) and fetal overgrowth syndrome such as Bechwith-Wiedemann syndrome and Sotos syndrome. This review provides an overview of syndromic and single gene disorders associated with fetal megacystis which is useful for genetic counseling at prenatal diagnosis of fetal megacystis.
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Affiliation(s)
- Chih-Ping Chen
- Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan; School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Institute of Clinical and Community Health Nursing, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Obstetrics and Gynecology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
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10
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Viti F, De Giorgio R, Ceccherini I, Ahluwalia A, Alves MM, Baldo C, Baldussi G, Bonora E, Borrelli O, Dall'Oglio L, De Coppi P, De Filippo C, de Santa Barbara P, Diamanti A, Di Lorenzo C, Di Maulo R, Galeone A, Gandullia P, Hashmi SK, Lacaille F, Lancon L, Leone S, Mahé MM, Molnar MJ, Palmitelli A, Perin S, Prato AP, Thapar N, Vassalli M, Heuckeroth RO. Multi-disciplinary Insights from the First European Forum on Visceral Myopathy 2022 Meeting. Dig Dis Sci 2023; 68:3857-3871. [PMID: 37650948 PMCID: PMC10517037 DOI: 10.1007/s10620-023-08066-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 07/28/2023] [Indexed: 09/01/2023]
Abstract
Visceral myopathy is a rare, life-threatening disease linked to identified genetic mutations in 60% of cases. Mostly due to the dearth of knowledge regarding its pathogenesis, effective treatments are lacking. The disease is most commonly diagnosed in children with recurrent or persistent disabling episodes of functional intestinal obstruction, which can be life threatening, often requiring long-term parenteral or specialized enteral nutritional support. Although these interventions are undisputedly life-saving as they allow affected individuals to avoid malnutrition and related complications, they also seriously compromise their quality of life and can carry the risk of sepsis and thrombosis. Animal models for visceral myopathy, which could be crucial for advancing the scientific knowledge of this condition, are scarce. Clearly, a collaborative network is needed to develop research plans to clarify genotype-phenotype correlations and unravel molecular mechanisms to provide targeted therapeutic strategies. This paper represents a summary report of the first 'European Forum on Visceral Myopathy'. This forum was attended by an international interdisciplinary working group that met to better understand visceral myopathy and foster interaction among scientists actively involved in the field and clinicians who specialize in care of people with visceral myopathy.
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Affiliation(s)
- Federica Viti
- Institute of Biophysics, National Research Council, Via De Marini, 6, 16149, Genoa, Italy.
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | | | - Arti Ahluwalia
- Centro di Ricerca 'E. Piaggio' and Department of Information Engineering, University of Pisa, Pisa, Italy
| | - Maria M Alves
- Department of Clinical Genetics, Erasmus University Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Chiara Baldo
- IRCCS Istituto Giannina Gaslini Pediatric Hospital, Genoa, Italy
| | - Giannina Baldussi
- 'Uniti per la P.I.P.O.' Patient Advocacy Organization, Brescia, Italy
| | - Elena Bonora
- Unit of Medical Genetics, Department of Medical and Surgical Sciences, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Osvaldo Borrelli
- Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Luigi Dall'Oglio
- Digestive Surgery and Endoscopy, Bambino Gesù Children's Research Hospital IRCCS, Rome, Italy
| | - Paolo De Coppi
- Pediatric Surgery, Great Ormond Street Hospital for Children, London, UK
| | - Carlotta De Filippo
- Institute of Agricultural Biology and Biotechnology of the National Research Council, Pisa, Italy
| | - Pascal de Santa Barbara
- Physiology and Experimental Medicine of the Heart and Muscles (PhyMedExp), University of Montpellier, INSERM, CNRS, Montpellier, France
| | | | - Carlo Di Lorenzo
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA
| | | | | | - Paolo Gandullia
- IRCCS Istituto Giannina Gaslini Pediatric Hospital, Genoa, Italy
| | - Sohaib K Hashmi
- Department of Pediatrics, The Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, PA, USA
| | - Florence Lacaille
- Pediatric Gastroenterology-Hepatology-Nutrition, Necker-Enfants Malades Hospital, Paris, France
| | - Laurence Lancon
- 'Association des POIC' Patient Advocacy Organization, Marseille, France
| | - Salvatore Leone
- AMICI ETS, Associazione Nazionale per le Malattie Infiammatorie Croniche dell'Intestino, Milan, Italy
| | - Maxime M Mahé
- Nantes Université, INSERM, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Nantes, France
| | | | | | - Silvia Perin
- Unit of Pediatric Surgery, Department of Women and Child Health, University of Padua, Padua, Italy
| | - Alessio Pini Prato
- Unit of Pediatric Surgery, 'St. Antonio e Biagio e Cesare Arrigo' Hospital, Alessandria, Italy
| | - Nikhil Thapar
- Stem Cell and Regenerative Medicine, GOS Institute of Child Health, University College London, London, UK
- Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
- Woolworths Centre for Child Nutrition Research, Queensland University of Technology, Brisbane, Australia
| | - Massimo Vassalli
- James Watt School of Engineering, University of Glasgow, Glasgow, UK
| | - Robert O Heuckeroth
- Department of Pediatrics, The Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, PA, USA
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11
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He X, Dong K, Shen J, Hu G, Mintz JD, Atawia RT, Zhao J, Chen X, Caldwell RW, Xiang M, Stepp DW, Fulton DJ, Zhou J. The Long Noncoding RNA Cardiac Mesoderm Enhancer-Associated Noncoding RNA (Carmn) Is a Critical Regulator of Gastrointestinal Smooth Muscle Contractile Function and Motility. Gastroenterology 2023; 165:71-87. [PMID: 37030336 PMCID: PMC10330198 DOI: 10.1053/j.gastro.2023.03.229] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 04/10/2023]
Abstract
BACKGROUND & AIMS Visceral smooth muscle cells (SMCs) are an integral component of the gastrointestinal (GI) tract that regulate GI motility. SMC contraction is regulated by posttranslational signaling and the state of differentiation. Impaired SMC contraction is associated with significant morbidity and mortality, but the mechanisms regulating SMC-specific contractile gene expression, including the role of long noncoding RNAs (lncRNAs), remain largely unexplored. Herein, we reveal a critical role of Carmn (cardiac mesoderm enhancer-associated noncoding RNA), an SMC-specific lncRNA, in regulating visceral SMC phenotype and contractility of the GI tract. METHODS Genotype-Tissue Expression and publicly available single-cell RNA sequencing (scRNA-seq) data sets from embryonic, adult human, and mouse GI tissues were interrogated to identify SMC-specific lncRNAs. The functional role of Carmn was investigated using novel green fluorescent protein (GFP) knock-in (KI) reporter/knock-out (KO) mice. Bulk RNA-seq and single nucleus RNA sequencing (snRNA-seq) of colonic muscularis were used to investigate underlying mechanisms. RESULTS Unbiased in silico analyses and GFP expression patterns in Carmn GFP KI mice revealed that Carmn is highly expressed in GI SMCs in humans and mice. Premature lethality was observed in global Carmn KO and inducible SMC-specific KO mice due to GI pseudo-obstruction and severe distension of the GI tract, with dysmotility in cecum and colon segments. Histology, GI transit, and muscle myography analysis revealed severe dilation, significantly delayed GI transit, and impaired GI contractility in Carmn KO vs control mice. Bulk RNA-seq of GI muscularis revealed that loss of Carmn promotes SMC phenotypic switching, as evidenced by up-regulation of extracellular matrix genes and down-regulation of SMC contractile genes, including Mylk, a key regulator of SMC contraction. snRNA-seq further revealed SMC Carmn KO not only compromised myogenic motility by reducing contractile gene expression but also impaired neurogenic motility by disrupting cell-cell connectivity in the colonic muscularis. These findings may have translational significance, because silencing CARMN in human colonic SMCs significantly attenuated contractile gene expression, including MYLK, and decreased SMC contractility. Luciferase reporter assays showed that CARMN enhances the transactivation activity of the master regulator of SMC contractile phenotype, myocardin, thereby maintaining the GI SMC myogenic program. CONCLUSIONS Our data suggest that Carmn is indispensable for maintaining GI SMC contractile function in mice and that loss of function of CARMN may contribute to human visceral myopathy. To our knowledge this is the first study showing an essential role of lncRNA in the regulation of visceral SMC phenotype.
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Affiliation(s)
- Xiangqin He
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Kunzhe Dong
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia; Immunology Center of Georgia, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Jian Shen
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guoqing Hu
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - James D Mintz
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Reem T Atawia
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Juanjuan Zhao
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Xiuxu Chen
- Department of Pathology and Laboratory Medicine, Loyola University Health System, Maywood, Illinois
| | - Robert W Caldwell
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Meixiang Xiang
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - David W Stepp
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - David J Fulton
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Jiliang Zhou
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia.
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12
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Viti F, Pramotton FM, Martufi M, Magrassi R, Pedemonte N, Nizzari M, Zanacchi FC, De Michele B, Alampi M, Zambito M, Santamaria G, Bajetto A, Sardar S, Tomati V, Gandullia P, Giampietro C, Florio T, Beltrame F, Vassalli M, Ceccherini I. Patient's dermal fibroblasts as disease markers for visceral myopathy. BIOMATERIALS ADVANCES 2023; 148:213355. [PMID: 36893487 DOI: 10.1016/j.bioadv.2023.213355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 02/09/2023] [Accepted: 02/19/2023] [Indexed: 06/18/2023]
Abstract
Visceral myopathy (VSCM) is a rare genetic disease, orphan of pharmacological therapy. VSCM diagnosis is not always straightforward due to symptomatology similarities with mitochondrial or neuronal forms of intestinal pseudo-obstruction. The most prevalent form of VSCM is associates with variants in the gene ACTG2, encoding the protein gamma-2 actin. Overall, VSCM is a mechano-biological disorder, in which different genetic variants lead to similar alterations to the contractile phenotype of enteric smooth muscles, resulting in the emergence of life-threatening symptoms. In this work we analyzed the morpho-mechanical phenotype of human dermal fibroblasts from patients affected with VSCM, demonstrating that they retain a clear signature of the disease when compared with different controls. We evaluated several biophysical traits of fibroblasts, and we show that a measure of cellular traction forces can be used as a non-specific biomarker of the disease. We propose that a simple assay based on traction forces could be designed to provide a valuable support for clinical decision or pre-clinical research.
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Affiliation(s)
- Federica Viti
- Istituto di Biofisica - Consiglio Nazionale delle Ricerche, Via De Marini 16, 16149 Genova, Italy.
| | - Francesca Micaela Pramotton
- EMPA, Swiss Federal Laboratories for Materials Science and Technology, Ueberlandstrasse 129, 8600 Dübendorf, Switzerland; ETH Zurich, The Institute for Mechanical Systems, Leonhardstrasse 21, 8092 Zürich, Switzerland
| | - Michela Martufi
- Istituto di Biofisica - Consiglio Nazionale delle Ricerche, Via De Marini 16, 16149 Genova, Italy; Dipartimento Medicina Interna, Sezione di Farmacologia, Università di Genova, viale Benedetto XV, 2, 16132 Genova, Italy
| | - Raffaella Magrassi
- Istituto di Biofisica - Consiglio Nazionale delle Ricerche, Via De Marini 16, 16149 Genova, Italy
| | - Nicoletta Pedemonte
- UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147 Genova, Italy
| | - Mario Nizzari
- Istituto di Biofisica - Consiglio Nazionale delle Ricerche, Via De Marini 16, 16149 Genova, Italy
| | | | - Benedetta De Michele
- Istituto di Biofisica - Consiglio Nazionale delle Ricerche, Via De Marini 16, 16149 Genova, Italy
| | - Manuela Alampi
- Department of Informatics, Bioengineering, Robotics and Systems Engineering, University of Genoa, Viale Causa, 13, 16145 Genova, Italy
| | - Martina Zambito
- Dipartimento Medicina Interna, Sezione di Farmacologia, Università di Genova, viale Benedetto XV, 2, 16132 Genova, Italy
| | - Giuseppe Santamaria
- UOSD Laboratorio di Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147 Genova, Italy
| | - Adriana Bajetto
- Dipartimento Medicina Interna, Sezione di Farmacologia, Università di Genova, viale Benedetto XV, 2, 16132 Genova, Italy
| | - Sabah Sardar
- Centre for the Cellular Microenvironment, James Watt School of Engineering, University of Glasgow, Oakfield avenue, G128LT Glasgow, UK
| | - Valeria Tomati
- UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147 Genova, Italy
| | - Paolo Gandullia
- UOC Pediatric Gastroenterology and Digestive Endoscopy, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147 Genova, Italy
| | - Costanza Giampietro
- EMPA, Swiss Federal Laboratories for Materials Science and Technology, Ueberlandstrasse 129, 8600 Dübendorf, Switzerland; ETH Zurich, The Institute for Mechanical Systems, Leonhardstrasse 21, 8092 Zürich, Switzerland
| | - Tullio Florio
- Dipartimento Medicina Interna, Sezione di Farmacologia, Università di Genova, viale Benedetto XV, 2, 16132 Genova, Italy; IRCCS Ospedale Policlinico San Martino, Largo rosanna benzi 10, 16132 Genova, Italy
| | - Francesco Beltrame
- Department of Informatics, Bioengineering, Robotics and Systems Engineering, University of Genoa, Viale Causa, 13, 16145 Genova, Italy
| | - Massimo Vassalli
- Centre for the Cellular Microenvironment, James Watt School of Engineering, University of Glasgow, Oakfield avenue, G128LT Glasgow, UK
| | - Isabella Ceccherini
- UOSD Laboratorio di Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147 Genova, Italy
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13
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Cai H, Xiao Y, Chen S, Lu Y, Du J, You Y, Zhu J, Zhou J, Cai W, Wang Y. Heterozygous Actg2 R257C mice mimic the phenotype of megacystis microcolon intestinal hypoperistalsis syndrome. Neurogastroenterol Motil 2023; 35:e14472. [PMID: 36264152 DOI: 10.1111/nmo.14472] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 07/27/2022] [Accepted: 09/08/2022] [Indexed: 01/01/2023]
Abstract
BACKGROUND Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare and serious congenital disorder with poor outcomes, where a heterozygous missense mutation is present in the ACTG2 gene. Here, we aimed to investigate the pathogenesis of ACTG2 in MMIHS. METHODS A cohort with 20 patients with MMIHS was screened. Actg2R257C heterozygous mutant mice were generated using the CRISPR/Cas9 system. Gastrointestinal (GI) motility, voluntary urination, collagen gel contraction, and G-actin/F-actin analysis were performed. KEY RESULTS The R257C variant of ACTG2 most frequently occurred in patients with MMIHS and demonstrated the typical symptoms of MMIHS. Actg2R257C heterozygous mutant mice had dilated intestines and bladders. The functional assay showed a prolonged total time of GI transit and decreased urine spot area. Collagen gel contraction assay and G-actin/F-actin analysis indicated that mutant mice showed reduced area of contraction of smooth muscle cells (SMCs) and impaired actin polymerization. CONCLUSIONS & INFERENCES A mouse model demonstrating MMIHS-like symptoms was generated. The Actg2R257C heterozygous variant impairs SMCs contraction by interfering with actin polymerization, leading to GI motility disorders.
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Affiliation(s)
- Hui Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yongtao Xiao
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.,Shanghai Institute of Pediatric Research, Shanghai, China
| | - Shanshan Chen
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Lu
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.,Shanghai Institute of Pediatric Research, Shanghai, China
| | - Jun Du
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.,Shanghai Institute of Pediatric Research, Shanghai, China
| | - Yaying You
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Zhu
- Shanghai Institute of Pediatric Research, Shanghai, China
| | - Jie Zhou
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.,Shanghai Institute of Pediatric Research, Shanghai, China
| | - Ying Wang
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.,Shanghai Institute of Pediatric Research, Shanghai, China
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14
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Bianco F, Lattanzio G, Lorenzini L, Mazzoni M, Clavenzani P, Calzà L, Giardino L, Sternini C, Costanzini A, Bonora E, De Giorgio R. Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction. Biomolecules 2022; 12:biom12121849. [PMID: 36551277 PMCID: PMC9776039 DOI: 10.3390/biom12121849] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/04/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is a typical clinical phenotype of severe gut dysmotility. This syndrome occurs due to changes altering the morpho-functional integrity of the intrinsic (enteric) innervation and extrinsic nerve supply (hence neuropathy), the interstitial cells of Cajal (ICC) (mesenchymopathy), and smooth muscle cells (myopathy). In the last years, several genes have been identified in different subsets of CIPO patients. The focus of this review is to cover the most recent update on enteric dysmotility related to CIPO, highlighting (a) forms with predominant underlying neuropathy, (b) forms with predominant myopathy, and (c) mitochondrial disorders with a clear gut dysfunction as part of their clinical phenotype. We will provide a thorough description of the genes that have been proven through recent evidence to cause neuro-(ICC)-myopathies leading to abnormal gut contractility patterns in CIPO. The discovery of susceptibility genes for this severe condition may pave the way for developing target therapies for enteric neuro-(ICC)-myopathies underlying CIPO and other forms of gut dysmotility.
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Affiliation(s)
- Francesca Bianco
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Giulia Lattanzio
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Luca Lorenzini
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Maurizio Mazzoni
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Paolo Clavenzani
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Laura Calzà
- IRET Foundation, 40064 Ozzano Emilia, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Luciana Giardino
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
- IRET Foundation, 40064 Ozzano Emilia, Italy
| | - Catia Sternini
- UCLA/DDRC, Division of Digestive Diseases, Departments Medicine and Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90001, USA
| | - Anna Costanzini
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Elena Bonora
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Correspondence: (E.B.); (R.D.G.); Tel.: +39-051-2094761 (E.B.); +39-0532-236631 (R.D.G.)
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
- Correspondence: (E.B.); (R.D.G.); Tel.: +39-051-2094761 (E.B.); +39-0532-236631 (R.D.G.)
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15
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Li N, Song YM, Zhang XD, Zhao XS, He XY, Yu LF, Zou DW. Pseudoileus caused by primary visceral myopathy in a Han Chinese patient with a rare MYH11 mutation: A case report. World J Clin Cases 2022; 10:12623-12630. [PMID: 36579105 PMCID: PMC9791514 DOI: 10.12998/wjcc.v10.i34.12623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/17/2022] [Accepted: 11/07/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Chronic intestinal pseudo-obstruction (CIPO) is a syndrome of intestinal motor dysfunction caused by intestinal nerve, muscle, and/or Cajal stromal cell lesions. CIPO is a serious category of gastrointestinal dynamic dysfunction, which can eventually lead to the death of patients with intestinal failure. Due to considerable phenotypic heterogeneity, the estimated incidence of CIPO is 1/476190 and 1/416666 in men and women, respectively. According to the etiology, CIPO can be divided into idiopathic and secondary, of which the latter is the most common, often secondary to tumor, virus infection, connective tissue disease, neurological diseases, and endocrine diseases. Idiopathic CIPO in the intestinal tract is divided into visceral myopathy, neuropathy, and stromal cell lesions according to the location. Surgery is usually not recommended for CIPO, because it often does not benefit patients with CIPO, and postoperative intestinal obstruction is likely to occur, which may even worsen the condition.
CASE SUMMARY Here, we describe the case of a 43-year-old male Han Chinese patient with a 15-year history of recurrent abdominal distention with no clear cause. The results of physical, biochemical, and other relevant examinations showed no clear abnormalities. Contrast-enhanced computed tomography (CT) indicated a large duodenum, clear expansion of the intestinal lumen, and CIPO. Whole exome sequencing (WES) of the patient and his mother confirmed the diagnosis of primary familial visceral myopathy type 2 chronic pseudoileus with a rare heterozygous gene mutation in MYH11. This is the second reported case of CIPO with a heterozygous MYH11 [NM_001040113.1: c.5819delC (p.Pro1940Hisfs*91)] mutation.
CONCLUSION This case report indicates that physicians can perform routine clinical examinations, CT, and WES to achieve a diagnosis and treatment of CIPO in early disease stages.
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Affiliation(s)
- Na Li
- Department of Geriatrics, Qinghai Provincial People’s Hospital, Xining 810007, Qinghai Province, China
| | - Yi-Ming Song
- Department of Gastroenterology, Fenghua District People’s Hospital, Ningbo 315000, Zhejiang Province, China
| | - Xian-Da Zhang
- Medical College, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xue-Song Zhao
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiang-Yi He
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Li-Fen Yu
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Duo-Wu Zou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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16
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Liu CY, Li JF, Yu QX, Zhen L, Li DZ. First trimester megacystis caused by a homozygous variant in MYL9. Eur J Obstet Gynecol Reprod Biol 2022; 278:199-200. [PMID: 36154779 DOI: 10.1016/j.ejogrb.2022.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/13/2022] [Accepted: 09/06/2022] [Indexed: 11/17/2022]
Affiliation(s)
- Chuan-Yong Liu
- Prenatal Diagnosis Center, Maoming People's Hospital, Maoming, Guangdong, China
| | - Jin-Fang Li
- Prenatal Diagnosis Center, Maoming People's Hospital, Maoming, Guangdong, China
| | - Qiu-Xia Yu
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center affiliated to Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Li Zhen
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center affiliated to Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Dong-Zhi Li
- Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center affiliated to Guangzhou Medical University, Guangzhou, Guangdong, China.
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17
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Fournier N, Fabre A. Smooth muscle motility disorder phenotypes: A systematic review of cases associated with seven pathogenic genes ( ACTG2, MYH11, FLNA, MYLK, RAD21, MYL9 and LMOD1). Intractable Rare Dis Res 2022; 11:113-119. [PMID: 36200034 PMCID: PMC9437995 DOI: 10.5582/irdr.2022.01060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/15/2022] [Accepted: 08/25/2022] [Indexed: 11/05/2022] Open
Abstract
Smooth muscle disorders affecting both the intestine and the bladder have been known for a decade. However, the recent discovery of genes associated with these dysfunctions has led to the description of several clinical phenotypes. We performed a systematic review of all published cases involving seven genes with pathogenic variants, ACTG2, MYH11, FLNA, MYLK, RAD21, MYL9 and LMOD1, and included 28 articles describing 112 patients and 5 pregnancies terminated before birth. The most commonly described mutations involved ACTG2 (75/112, 67% of patients), MYH11 (14%) and FLNA (13%). Twenty-seven patients (28%) died at a median age of 14.5 months. Among the 76 patients for whom this information was available, 10 (13%) had isolated chronic intestinal pseudo-obstruction (CIPO), 17 (22%) had isolated megacystis, and 48 (63%) had combined CIPO and megacystis. The respective proportions of these phenotypes were 9%, 20% and 71% among the 56 patients with ACTG2 mutations, 20%, 20% and 60% among the 10 patients with MYH11 mutations and 50%, 50% and 0% among the 7 patients with FLNA mutations.
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Affiliation(s)
- Ninon Fournier
- APHM, Timone Enfant, Pediatric Multidisciplinary Department, Marseille, France
| | - Alexandre Fabre
- APHM, Timone Enfant, Pediatric Multidisciplinary Department, Marseille, France
- Aix-Marseille Université, INSERM, GMGF, Marseille, France
- Address correspondence to:Alexandre Fabre, Pediatric Multidisciplinary Department, Timone Enfant Hospital, APHM, Aix-Marseille University, 264 Rue Saint Pierre 13005 Marseille, France. E-mail:
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18
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Huang CH, Schuring J, Skinner JP, Mok L, Chong MMW. MYL9 deficiency is neonatal lethal in mice due to abnormalities in the lung and the muscularis propria of the bladder and intestine. PLoS One 2022; 17:e0270820. [PMID: 35802750 PMCID: PMC9269942 DOI: 10.1371/journal.pone.0270820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 06/20/2022] [Indexed: 11/19/2022] Open
Abstract
Class II myosin complexes are responsible for muscle contraction as well as other non-sarcomeric contractile functions in cells. Myosin heavy chain molecules form the core of these structures, while light chain molecules regulate their stability and function. MYL9 is a light chain isoform that is thought to regulate non-sarcomeric myosin. However, whether this in only in specific cell types or in all cells remains unclear. To address this, we generated MYL9 deficient mice. These mice die soon after birth with abnormalities in multiple organs. All mice exhibited a distended bladder, shortening of the small intestine and alveolar overdistension in the lung. The Myl9 allele in these mice included a LacZ reporter knockin that allowed for mapping of Myl9 gene expression. Using this reporter, we show that MYL9 expression is restricted to the muscularis propria of the small intestine and bladder, as well as in the smooth muscle layer of the bronchi in the lung and major bladder vessels in all organs. This suggests that MYL9 is important for the function of smooth muscle cells in these organs. Smooth muscle dysfunction is therefore likely to be the cause of the abnormalities observed in the intestine, bladder and lung of MYL9 deficient mice and the resulting neonatal lethality.
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Affiliation(s)
- Chu-Han Huang
- St Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
- Department of Medicine (St Vincent’s), University of Melbourne, Fitzroy, VIC, Australia
| | - Joyce Schuring
- St Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
- HAN University of Applied Sciences, Nijmegen, The Netherlands
| | | | - Lawrence Mok
- St Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
- Department of Medicine (St Vincent’s), University of Melbourne, Fitzroy, VIC, Australia
| | - Mark M. W. Chong
- St Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
- Department of Medicine (St Vincent’s), University of Melbourne, Fitzroy, VIC, Australia
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19
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Liu K, Lu L, Chen S, Gu B, Cai H, Wang Y, Cai W. Loss-of-function variants within LMOD1 actin-binding site 2 cause pediatric intestinal pseudo-obstruction by impairing protein stability and actin nucleation. FASEB J 2022; 36:e22194. [PMID: 35170814 DOI: 10.1096/fj.202101395r] [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: 09/02/2021] [Revised: 01/12/2022] [Accepted: 01/21/2022] [Indexed: 11/11/2022]
Abstract
The leiomodin1 (LMOD1) gene, encoding a potent actin nucleator, was recently reported as a potential pathogenic gene of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, OMIM 619362). However, only a single patient has been reported to have LMOD1 mutations, and the underlying pathogenic mechanism remains unknown. Here, we described a male infant with LMOD1 mutations presenting typical symptoms of pediatric intestinal pseudo-obstruction (PIPO) but without megacystis and microcolon. Two compound heterozygous missense variants (c.1106C>T, p.T369M; c.1262G>A, p.R421H) were identified, both affecting highly conserved amino acid residues within the second actin-binding site (ABS2) domain of LMOD1. Expression analysis showed that both variants resulted in significantly reduced protein amounts, especially for p.T369M, which was almost undetectable. The reduction was only partially rescued by the proteasome inhibitor MG-132, indicating that there might be proteasome-independent pathways involved in the degradation of the mutant proteins. Molecular modeling showed that variant p.T369M impaired the local protein conformation of the ABS2 domain, while variant p.R421H directly impaired the intermolecular interaction between ABS2 and actin. Accordingly, both variants significantly damaged LMOD1-mediated actin nucleation. These findings provide further human genetic evidence supporting LMOD1 as a pathogenic gene underlying visceral myopathy including PIPO and MMIHS, strengthen the critical role of ABS2 domain in LMOD1-mediated actin nucleation, and moreover, reveal an unrecognized role of ABS2 in protein stability.
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Affiliation(s)
- Keqiang Liu
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute for Pediatric Research, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Lina Lu
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shanshan Chen
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Beilin Gu
- Shanghai Institute for Pediatric Research, Shanghai, China
| | - Hui Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Wang
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute for Pediatric Research, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.,Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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20
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Bianco F, Bonora E, Lattanzio G, Clavenzani P, Guarino M, Mazzoni M, Baldassarro VA, Lorenzini L, Caio G, Stanghellini V, Sternini C, Farrugia G, Giardino L, Calzà L, De Giorgio R. Clinical and Pathological Features of Severe Gut Dysmotility. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:9-17. [PMID: 36587142 DOI: 10.1007/978-3-031-05843-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Severe gut motility disorders are characterized by ineffective propulsion of intestinal contents. As a result, patients often develop extremely uncomfortable symptoms, ranging from nausea and vomiting along with alterations of bowel habits, up to radiologically confirmed subobstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is a typical clinical phenotype of severe gut dysmotility due to morphological and functional alterations of the intrinsic (enteric) innervation and extrinsic nerve supply (hence neuropathy), interstitial cells of Cajal (ICCs) (mesenchymopathy), and smooth muscle cells (myopathy). In this chapter, we highlight some molecular mechanisms of CIPO and review the clinical phenotypes and the genetics of the different types of CIPO. Specifically, we will detail the role of some of the most representative genetic mutations involving RAD21, LIG3, and ACTG2 to provide a better understanding of CIPO and related underlying neuropathic or myopathic histopathological abnormalities. This knowledge may unveil targeted strategies to better manage patients with such severe disease.
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Affiliation(s)
- Francesca Bianco
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Department of Veterinary Sciences University of Bologna, Bologna, Italy
| | - Elena Bonora
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giulia Lattanzio
- Department of Veterinary Sciences University of Bologna, Bologna, Italy
| | - Paolo Clavenzani
- Department of Veterinary Sciences University of Bologna, Bologna, Italy
| | - Matteo Guarino
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Maurizio Mazzoni
- Department of Veterinary Sciences University of Bologna, Bologna, Italy
| | | | | | - Giacomo Caio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Vincenzo Stanghellini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Catia Sternini
- UCLA/DDRC, Division of Digestive Diseases, Departments Medicine and Neurobiology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Gianrico Farrugia
- Enteric Neuroscience Program (ENSP), Mayo Clinic, Rochester, MN, USA
| | | | | | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy.
- Unit of Internal Medicine, St. Anna Hospital, Ferrara, Italy.
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21
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You Y, Liu T, Shen J. Research progress in myosin light chain 9 in malignant tumors. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2021; 46:1153-1158. [PMID: 34911847 PMCID: PMC10930228 DOI: 10.11817/j.issn.1672-7347.2021.200814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Indexed: 11/03/2022]
Abstract
Myosin light chain 9 (MYL9) is a regulatory light chain of myosin, which plays an important role in various biological processes including cell contraction, proliferation and invasion. MYL9 expresses abnormally in several malignancies including lung cancer, breast cancer, prostate cancer, malignant melanoma and others, which is closely related to the poor prognosis, but the clinical significance for its expression varies with different types of cancer tissues. Further elucidating the molecular mechanism of MYL9 in various types of malignant tumor metastasis is of great significance for cancer prevention and treatment. At the same time, as a molecular marker and potential target, MYL9 may have great clinical value in the early diagnosis, prognosis prediction, and targeted treatment of malignant tumors.
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Affiliation(s)
- Yimeng You
- Fujian Institute of Hematology; Fujian Provincial Key Laboratory on Hematology; Department of Hematology, Union Hospital Affiliated to Fujian Medical University, Fuzhou 350001, China.
| | - Tingbo Liu
- Fujian Institute of Hematology; Fujian Provincial Key Laboratory on Hematology; Department of Hematology, Union Hospital Affiliated to Fujian Medical University, Fuzhou 350001, China
| | - Jianzhen Shen
- Fujian Institute of Hematology; Fujian Provincial Key Laboratory on Hematology; Department of Hematology, Union Hospital Affiliated to Fujian Medical University, Fuzhou 350001, China.
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22
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Hashmi SK, Ceron RH, Heuckeroth RO. Visceral myopathy: clinical syndromes, genetics, pathophysiology, and fall of the cytoskeleton. Am J Physiol Gastrointest Liver Physiol 2021; 320:G919-G935. [PMID: 33729000 PMCID: PMC8285581 DOI: 10.1152/ajpgi.00066.2021] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Visceral smooth muscle is a crucial component of the walls of hollow organs like the gut, bladder, and uterus. This specialized smooth muscle has unique properties that distinguish it from other muscle types and facilitate robust dilation and contraction. Visceral myopathies are diseases where severe visceral smooth muscle dysfunction prevents efficient movement of air and nutrients through the bowel, impairs bladder emptying, and affects normal uterine contraction and relaxation, particularly during pregnancy. Disease severity exists along a spectrum. The most debilitating defects cause highly dysfunctional bowel, reduced intrauterine colon growth (microcolon), and bladder-emptying defects requiring catheterization, a condition called megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). People with MMIHS often die early in childhood. When the bowel is the main organ affected and microcolon is absent, the condition is known as myopathic chronic intestinal pseudo-obstruction (CIPO). Visceral myopathies like MMIHS and myopathic CIPO are most commonly caused by mutations in contractile apparatus cytoskeletal proteins. Here, we review visceral myopathy-causing mutations and normal functions of these disease-associated proteins. We propose molecular, cellular, and tissue-level models that may explain clinical and histopathological features of visceral myopathy and hope these observations prompt new mechanistic studies.
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Affiliation(s)
- Sohaib Khalid Hashmi
- 1Department of Pediatrics, The Children’s Hospital
of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, Pennsylvania,2Department of Bioengineering, The University of Pennsylvania School of Engineering and Applied Science, Philadelphia, Pennsylvania
| | - Rachel Helen Ceron
- 1Department of Pediatrics, The Children’s Hospital
of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, Pennsylvania,3Department of Physiology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Robert O. Heuckeroth
- 1Department of Pediatrics, The Children’s Hospital
of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, Pennsylvania
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23
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Prathapan KM, King DE, Raghu VK, Ackerman K, Presel T, Yaworski JA, Ganoza A, Bond G, Sevilla WMA, Rudolph JA, Alissa F. Megacystis Microcolon Intestinal Hypoperistalsis Syndrome: A Case Series With Long-term Follow-up and Prolonged Survival. J Pediatr Gastroenterol Nutr 2021; 72:e81-e85. [PMID: 33264186 PMCID: PMC9124153 DOI: 10.1097/mpg.0000000000003008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Describe clinical characteristics, management, and outcome in a cohort of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) patients. METHODS We conducted a retrospective chart review of MMIHS patients followed at a large transplant and intestinal rehabilitation center over a period of 17 years. RESULTS We identified 25 patients with MMIHS (68% girls, 13 transplanted). One transplanted and 1 nontransplanted patient were lost to follow-up. We estimated 100, 100, and 86% for 5-, 10-, and 20-year survival, respectively, with only 1 death. Of the 22 patients alive at the time of study (11 transplanted, 11 nontransplanted), median age was 9.2 years (range 2.7-22.9 years). Longest posttransplant follow-up was 16 years. Seventeen patients had available prenatal imaging reports; all showed distended bladder. Eight had genetic testing (5, ACTG2; 2, MYH11; 1, MYL9). Almost all patients had normal growth with median weight z-score -0.77 (interquartile range -1.39 to 0.26), height z score -1.2 (-2.04 to -0.48) and body mass index z-score 0.23 (-0.37 to 0.93) with no statistical difference between transplanted and nontransplanted patients. All nontransplanted patients were on parenteral nutrition with minimal/no feeds, and all except 1 of the transplanted patients were on full enteral feeds. Recent average bilirubin, INR, albumin, and creatinine fell within the reference ranges. CONCLUSIONS This is the largest single-center case series with the longest duration of follow-up for MMIHS patients. In the current era of improved intestinal rehabilitation and transplantation, MMIHS patients have excellent outcomes in survival, growth, and liver function. This observation contradicts previous reports and should alter counselling and management decisions in these patients at diagnosis.
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Affiliation(s)
- Krishnapriya Marangattu Prathapan
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Dale E. King
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Vikram Kalathur Raghu
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Kimberly Ackerman
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Tracey Presel
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Jane Anne Yaworski
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Armando Ganoza
- Hillman Center for Pediatric Liver Transplantation, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Geoffrey Bond
- Hillman Center for Pediatric Liver Transplantation, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Wednesday Marie A. Sevilla
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Jeffrey A. Rudolph
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Feras Alissa
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
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24
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Matera I, Bordo D, Di Duca M, Lerone M, Santamaria G, Pongiglione M, Lezo A, Diamanti A, Spagnuolo MI, Pini Prato A, Alberti D, Mattioli G, Gandullia P, Ceccherini I. Novel ACTG2 variants disclose allelic heterogeneity and bi-allelic inheritance in pediatric chronic intestinal pseudo-obstruction. Clin Genet 2020; 99:430-436. [PMID: 33294969 DOI: 10.1111/cge.13895] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/13/2022]
Abstract
Variants in the ACTG2 gene, encoding a protein crucial for correct enteric muscle contraction, have been found in patients affected with chronic intestinal pseudo-obstruction, either congenital or late-onset visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Here we report about ten pediatric and one adult patients, from nine families, carrying ACTG2 variants: four show novel still unpublished missense variants, including one that is apparently transmitted according to a recessive mode of inheritance. Four of the remaining five probands carry variants affecting arginine residues, that have already been associated with a severe phenotype. A de novo occurrence of the variants could be confirmed in six of these families. Since a genotype-phenotype correlation is affected by extrinsic factors, such as, diagnosis delay, quality of clinical management, and intra-familial variability, we have undertaken 3D molecular modeling to get further insights into the effects of the variants here described. The present findings and further ACTG2 testing of patients presenting with intestinal pseudo-obstruction, will improve our understanding of visceral myopathies, including implications in the prognosis and genetic counseling of this set of severe disorders.
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Affiliation(s)
- Ivana Matera
- UOSD Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Genoa, Italia, Italy
| | | | - Marco Di Duca
- UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Genoa, Italia, Italy
| | - Margherita Lerone
- UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Genoa, Italia, Italy
| | - Giuseppe Santamaria
- UOSD Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Genoa, Italia, Italy
| | - Marta Pongiglione
- UOC Radiologia, IRCCS Istituto Giannina Gaslini, Genoa, Italia, Italy
| | - Antonella Lezo
- Dietetics and Clinical Nutrition Unit, Children's Hospital Regina Margherita, Torino, Italy
| | - Antonella Diamanti
- UOS Nutrizione Artificiale, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | | | - Alessio Pini Prato
- UO Chirurgia Pediatrica, AON SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Daniele Alberti
- UO Chirurgia Pediatrica, ASST- Spedali Civili di Brescia, Brescia, Italy
| | | | - Paolo Gandullia
- UOC Gastroenterologia. IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Isabella Ceccherini
- UOSD Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Genoa, Italia, Italy
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25
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Sun J, Qiao YN, Tao T, Zhao W, Wei LS, Li YQ, Wang W, Wang Y, Zhou YW, Zheng YY, Chen X, Pan HC, Zhang XN, Zhu MS. Distinct Roles of Smooth Muscle and Non-muscle Myosin Light Chain-Mediated Smooth Muscle Contraction. Front Physiol 2020; 11:593966. [PMID: 33424621 PMCID: PMC7793928 DOI: 10.3389/fphys.2020.593966] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/18/2020] [Indexed: 12/17/2022] Open
Abstract
Both smooth muscle (SM) and non-muscle (NM) myosin II are expressed in hollow organs such as the bladder and uterus, but their respective roles in contraction and corresponding physiological functions remain to be determined. In this report, we assessed their roles by analyzing mice deficient of Myl9, a gene encoding the SM myosin regulatory light chain (SM RLC). We find that global Myl9-deficient bladders contracted with an apparent sustained phase, despite no initial phase. This sustained contraction was mediated by NM myosin RLC (NM RLC) phosphorylation by myosin light chain kinase (MLCK). NM myosin II was expressed abundantly in the uterus and young mice bladders, of which the force was accordingly sensitive to NM myosin inhibition. Our findings reveal distinct roles of SM RLC and NM RLC in SM contraction.
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Affiliation(s)
- Jie Sun
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Yan-Ning Qiao
- Key Laboratory of MOE for Modern Teaching Technology, Shaanxi Normal University, Xi'an, China
| | - Tao Tao
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Wei Zhao
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Li-Sha Wei
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Ye-Qiong Li
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Wei Wang
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Ye Wang
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Yu-Wei Zhou
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Yan-Yan Zheng
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Xin Chen
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Hong-Chun Pan
- College of Life Sciences, Anhui Normal University, Wuhu, China
| | - Xue-Na Zhang
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
| | - Min-Sheng Zhu
- Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China
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26
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Kandler JL, Sklirou E, Woerner A, Walsh L, Cox E, Xue Y. Compound heterozygous loss of function variants in MYL9 in a child with megacystis-microcolon-intestinal hypoperistalsis syndrome. Mol Genet Genomic Med 2020; 8:e1516. [PMID: 33031641 PMCID: PMC7667357 DOI: 10.1002/mgg3.1516] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/10/2020] [Indexed: 12/13/2022] Open
Abstract
Megacystis–microcolon–intestinal hypoperistalsis syndrome (MMIHS), or “visceral myopathy,” is a severe early onset disorder characterized by impaired muscle contractility in the bladder and intestines. Five genes are linked to MMIHS: primarily ACTG2, but also LMOD1, MYH11, MYLK, and MYL9. Here we describe a three‐year‐old girl with bilateral hydronephrosis diagnosed at 20 weeks gestation and congenital mydriasis (both of which have been previously observed among individuals with MMIHS). A clinical diagnosis of MMIHS was made based upon the presence of megacystis, lack of urinary bladder peristalsis, and intestinal pseudo‐obstruction. After initial testing of ACTG2 was negative, further sequencing and deletion/duplication testing was performed on the LMOD1, MYH11,MYLK, and MYL9 genes. We identified two heterozygous loss of function variants in MYL9: an exon 4 deletion and a nine base pair deletion that removes the canonical splicing donor site at exon 2 (NM_006097.5:c.184+2_184+10del). Parental testing confirmed these variants to be in trans in our proband. To our knowledge, only one other individual with MMIHS has biallelic mutations in MYL9 (a homozygous deletion encompassing exon 4). We suggest MYL9 be targeted on genetic testing panels for MMIHS, smooth muscle myopathies, and cardiovascular phenotypes.
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Affiliation(s)
| | - Evgenia Sklirou
- Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Audrey Woerner
- Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Leslie Walsh
- Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Yuan Xue
- Fulgent Genetics, Atlanta, Georgia, USA
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27
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Khan SA, He J, Deng S, Zhang H, Liu G, Li S, Tang D, Zhang J, Shu Y, Wu H. Integrated analysis of mRNA and miRNA expression profiles reveals muscle growth differences between fast- and slow-growing king ratsnakes (Elaphe carinata). Comp Biochem Physiol B Biochem Mol Biol 2020; 248-249:110482. [DOI: 10.1016/j.cbpb.2020.110482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/18/2020] [Accepted: 07/20/2020] [Indexed: 10/23/2022]
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Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP. Int J Mol Sci 2020; 21:ijms21186715. [PMID: 32937737 PMCID: PMC7555576 DOI: 10.3390/ijms21186715] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 12/21/2022] Open
Abstract
The activity-dependent neuroprotective protein (ADNP), a double-edged sword, sex-dependently regulates multiple genes and was previously associated with the control of early muscle development and aging. Here we aimed to decipher the involvement of ADNP in versatile muscle gene expression patterns in correlation with motor function throughout life. Using quantitative RT-PCR we showed that Adnp+/− heterozygous deficiency in mice resulted in aberrant gastrocnemius (GC) muscle, tongue and bladder gene expression, which was corrected by the Adnp snippet, drug candidate, NAP (CP201). A significant sexual dichotomy was discovered, coupled to muscle and age-specific gene regulation. As such, Adnp was shown to regulate myosin light chain (Myl) in the gastrocnemius (GC) muscle, the language acquisition gene forkhead box protein P2 (Foxp2) in the tongue and the pituitary-adenylate cyclase activating polypeptide (PACAP) receptor PAC1 mRNA (Adcyap1r1) in the bladder, with PACAP linked to bladder function. A tight age regulation was observed, coupled to an extensive correlation to muscle function (gait analysis), placing ADNP as a muscle-regulating gene/protein.
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29
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Billon C, Molin A, Poirsier C, Clemenson A, Dauge C, Grelet M, Sigaudy S, Patrier S, Goldenberg A, Layet V, Tantau J, Fleury C, Liard A, Diguet A, Fritih R, Verspyck E, Rendu J, Boutaud L, Tessier A, Thomas S, Razavi F, Achaiaa A, Elkhartoufi N, Hakkakian L, Magnin E, Bôle-Feysot C, Masson C, Ville Y, Roth P, Prieur F, Bessieres B, Bonniere M, Attie-Bitach T. Fetal megacystis-microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene. Clin Genet 2020; 98:261-273. [PMID: 32621347 DOI: 10.1111/cge.13801] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 06/24/2020] [Accepted: 06/25/2020] [Indexed: 12/13/2022]
Abstract
Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non-obstructed urinary bladder, a microcolon and intestinal hypo- or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant in MYH11 and a previously described homozygous deletion in MYL9. Finally, we identified compound heterozygous variants in a novel candidate gene, PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss-of-function of this protein affects the contractility of smooth muscle tissues, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.
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Affiliation(s)
- Clarisse Billon
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France.,Département de Génétique, Hôpital Européen Georges Pompidou, APHP, Paris, France
| | - Arnaud Molin
- Département de Génétique, Normandie Université, UNICAEN, CHU de Caen Normandie, Caen, France
| | | | - Alix Clemenson
- Service d'Anatomie et Cytotologie Pathologique, CHU de Saint Etienne, Saint Etienne, France
| | - Coralie Dauge
- Department of Pathology, University Hospital, Caen, France
| | - Maude Grelet
- Département de Génétique Médicale, Hôpital de la Timone, APHM, Marseille, France
| | - Sabine Sigaudy
- Département de Génétique Médicale, Hôpital de la Timone, APHM, Marseille, France
| | - Sophie Patrier
- Service d'Anatomie Pathologique, CHU Ch. Nicolle, Rouen, France
| | - Alice Goldenberg
- centre de référence anomalies du développement et syndromes malformatifs, CHU de Rouen, Centre Normand de Génomique et de Médecine Personnalisée, France
| | - Valérie Layet
- Consultations de génétique, Groupe Hospitalier du Havre, Le Havre, France
| | - Julia Tantau
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Clémence Fleury
- Department of Pathology, Robert-Debré University Hospital, Reims, France
| | - Agnès Liard
- Département de chirurgie infantile, Chu de Rouen, Rouen, France
| | - Alain Diguet
- Laboratoire d'anatomie pathologique, pavillon Jacques-Delarue, CHU de Rouen, Rouen, France
| | - Radia Fritih
- Pathology Department, Hôpital de la Timone, APHM, Marseille, France
| | - Eric Verspyck
- Department of Obstetrics and Gynecology, Rouen University Hospital, Rouen, France
| | - John Rendu
- Unité Médicale de Génétique Moléculaire, Inserm U1216, CHU de Grenoble, Grenoble, France
| | - Lucile Boutaud
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France.,INSERM UMR 1163, Université de Paris, Imagine Institute, Paris, France
| | - Aude Tessier
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Sophie Thomas
- INSERM UMR 1163, Université de Paris, Imagine Institute, Paris, France
| | - Ferechté Razavi
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Amale Achaiaa
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Nadia Elkhartoufi
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Leila Hakkakian
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Eglantine Magnin
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | | | - Cécile Masson
- Bioinformatics Platform, INSERM UMR 1163, Institut Imagine, Paris, France
| | - Yves Ville
- Service d'Obstétrique, Maternité, Chirurgie, Médecine et Imagerie Fœtales, Hôpital Necker-Enfants Malades, AP-HP, Centre - Université de Paris, Paris, France
| | - Philippe Roth
- Service d'Obstétrique, Maternité, Chirurgie, Médecine et Imagerie Fœtales, Hôpital Necker-Enfants Malades, AP-HP, Centre - Université de Paris, Paris, France
| | - Fabienne Prieur
- Service de génétique, Hôpital Nord CHU Saint-Etienne, Saint Etienne, France
| | - Bettina Bessieres
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Maryse Bonniere
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France
| | - Tania Attie-Bitach
- Service d'Histologie-Embryologie-Cytogénétique, Unité d'Embryofoetopathologie, Hôpital Necker-Enfants Malades, APHP, Paris, France.,INSERM UMR 1163, Université de Paris, Imagine Institute, Paris, France
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30
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Assia Batzir N, Kishor Bhagwat P, Larson A, Coban Akdemir Z, Bagłaj M, Bofferding L, Bosanko KB, Bouassida S, Callewaert B, Cannon A, Enchautegui Colon Y, Garnica AD, Harr MH, Heck S, Hurst ACE, Jhangiani SN, Isidor B, Littlejohn RO, Liu P, Magoulas P, Mar Fan H, Marom R, McLean S, Nezarati MM, Nugent KM, Petersen MB, Rocha ML, Roeder E, Smigiel R, Tully I, Weisfeld-Adams J, Wells KO, Posey JE, Lupski JR, Beaudet AL, Wangler MF. Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy. Hum Mutat 2020; 41:641-654. [PMID: 31769566 PMCID: PMC7720429 DOI: 10.1002/humu.23960] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 10/04/2019] [Accepted: 11/06/2019] [Indexed: 02/06/2023]
Abstract
Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.
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Affiliation(s)
- Nurit Assia Batzir
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Texas Children's Hospital, Houston, Texas
| | - Pranjali Kishor Bhagwat
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas
| | - Austin Larson
- Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, Colorado
| | - Zeynep Coban Akdemir
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Maciej Bagłaj
- Department of Pediatric Surgery and Urology, Wroclaw Medical University, Wroclaw, Poland
| | - Leon Bofferding
- Département de Pédiatrie Néonatologie, Kannerklinik, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg
| | - Katherine B Bosanko
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Skander Bouassida
- Humboldt Clinic, Vivantes Health Network GmbH, Charité Academic Teaching Hospital, Medical University of Berlin, Berlin, Germany
| | - Bert Callewaert
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University Hospital, Ghent, Belgium
| | - Ashley Cannon
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Yazmin Enchautegui Colon
- Inherited Metabolic Diseases Clinic, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado
| | - Adolfo D Garnica
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Margaret H Harr
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Sandra Heck
- Département de Pédiatrie Néonatologie, Kannerklinik, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg
| | - Anna C E Hurst
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama
| | | | - Bertrand Isidor
- CHU de Nantes, Service de Génétique Médicale, Nantes 44093 Cedex 1, Nantes, France
| | - Rebecca O Littlejohn
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas
| | - Pengfei Liu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Pilar Magoulas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Texas Children's Hospital, Houston, Texas
| | - Helen Mar Fan
- Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Ronit Marom
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Texas Children's Hospital, Houston, Texas
| | - Scott McLean
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas
| | - Marjan M Nezarati
- Genetics Program, North York General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Kimberly M Nugent
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas
| | | | - Maria L Rocha
- Humboldt Clinic, Vivantes Health Network GmbH, Charité Academic Teaching Hospital, Medical University of Berlin, Berlin, Germany
| | - Elizabeth Roeder
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas
| | - Robert Smigiel
- Department of Pediatrics, Division of Pediatrics and Rare Disorders, Wroclaw Medical University, Wroclaw, Poland
| | - Ian Tully
- Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - James Weisfeld-Adams
- Inherited Metabolic Diseases Clinic, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado
| | - Katerina O Wells
- Department of Surgery, Division of Colorectal Surgery, Baylor University Medical Center, Dallas, Texas
| | - Jennifer E Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - James R Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Texas Children's Hospital, Houston, Texas
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Arthur L Beaudet
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Texas Children's Hospital, Houston, Texas
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Michael F Wangler
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Texas Children's Hospital, Houston, Texas
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas
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31
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Gilbert MA, Schultz-Rogers L, Rajagopalan R, Grochowski CM, Wilkins BJ, Biswas S, Conlin LK, Fiorino KN, Dhamija R, Pack MA, Klee EW, Piccoli DA, Spinner NB. Protein-elongating mutations in MYH11 are implicated in a dominantly inherited smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease. Hum Mutat 2020; 41:973-982. [PMID: 31944481 DOI: 10.1002/humu.23986] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 12/17/2019] [Accepted: 01/13/2020] [Indexed: 12/12/2022]
Abstract
Gastrointestinal motility disorders include a spectrum of mild to severe clinical phenotypes that are caused by smooth muscle dysfunction. We investigated the genetic etiology of severe esophageal, gastric, and colonic dysmotility in two unrelated families with autosomal dominant disease presentation. Using exome sequencing, we identified a 2 base pair insertion at the end of the myosin heavy chain 11 (MYH11) gene in all affected members of Family 1 [NM_001040113:c.5819_5820insCA(p.Gln1941Asnfs*91)] and a 1 base pair deletion at the same genetic locus in Proband 2 [NM_001040113:c.5819del(p.Pro1940Hisfs*91)]. Both variants are predicted to result in a similarly elongated protein product. Heterozygous dominant negative MYH11 pathogenic variants have been associated with thoracic aortic aneurysm and dissection while biallelic null alleles have been associated with megacystis microcolon intestinal hypoperistalsis syndrome. This report highlights heterozygous protein-elongating MYH11 variants affecting the SM2 isoforms of MYH11 as a cause for severe gastrointestinal dysmotility, and we hypothesize that the mechanistic pathogenesis of this disease, dominant hypercontractile loss-of-function, is distinct from those implicated in other diseases involving MYH11 dysfunction.
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Affiliation(s)
- Melissa A Gilbert
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Laura Schultz-Rogers
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.,Department of Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Ramakrishnan Rajagopalan
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Christopher M Grochowski
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Benjamin J Wilkins
- Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sawona Biswas
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Laura K Conlin
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kristin N Fiorino
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,The Suzi and Scott Lustgarten Center for GI Motility, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Radhika Dhamija
- Department of Medical Genetics, Mayo Clinic, Phoenix, Arizona
| | - Michael A Pack
- Division of Gastroenterology, Department of Medicine, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Cell and Developmental Biology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Eric W Klee
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.,Department of Health Sciences, Mayo Clinic, Rochester, Minnesota.,Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota
| | - David A Piccoli
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,The Suzi and Scott Lustgarten Center for GI Motility, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nancy B Spinner
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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32
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Wang H, Zhu H, Zhu W, Xu Y, Wang N, Han B, Song H, Qiao J. Bioinformatic Analysis Identifies Potential Key Genes in the Pathogenesis of Turner Syndrome. Front Endocrinol (Lausanne) 2020; 11:104. [PMID: 32210915 PMCID: PMC7069359 DOI: 10.3389/fendo.2020.00104] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 02/18/2020] [Indexed: 12/29/2022] Open
Abstract
Background: Turner syndrome (TS) is a sex chromosome aneuploidy with a variable spectrum of symptoms including short stature, ovarian failure and skeletal abnormalities. The etiology of TS is complex, and the mechanisms driving its pathogenesis remain unclear. Methods: In our study, we used the online Gene Expression Omnibus (GEO) microarray expression profiling dataset GSE46687 to identify differentially expressed genes (DEGs) between monosomy X TS patients and normal female individuals. The relevant data on 26 subjects with TS (45,XO) and 10 subjects with the normal karyotype (46,XX) was investigated. Then, tissue-specific gene expression, functional enrichment, and protein-protein interaction (PPI) network analyses were performed, and the key modules were identified. Results: In total, 25 upregulated and 60 downregulated genes were identified in the differential expression analysis. The tissue-specific gene expression analysis of the DEGs revealed that the system with the most highly enriched tissue-specific gene expression was the hematologic/immune system, followed by the skin/skeletal muscle and neurologic systems. The PPI network analysis, construction of key modules and manual screening of tissue-specific gene expression resulted in the identification of the following five genes of interest: CD99, CSF2RA, MYL9, MYLPF, and IGFBP2. CD99 and CSF2RA are involved in the hematologic/immune system, MYL9 and MYLPF are related to the circulatory system, and IGFBP2 is related to skeletal abnormalities. In addition, several genes of interest with possible roles in the pathogenesis of TS were identified as being associated with the hematologic/immune system or metabolism. Conclusion: This discovery-driven analysis may be a useful method for elucidating novel mechanisms underlying TS. However, more experiments are needed to further explore the relationships between these genes and TS in the future.
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Affiliation(s)
- Hao Wang
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Zhu
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenjiao Zhu
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Xu
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Nan Wang
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Han
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huaidong Song
- Research Centre for Clinical Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Qiao
- Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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33
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Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss current knowledge on pediatric intestinal pseudo-obstruction. We will also review new mutations that have been identified through advancement in genetic testing, allowing for a better understanding of the underlying mechanisms of intestinal dysmotility and potential etiologies. RECENT FINDINGS With the advancements in genetic testing, new mutations have been identified in the diagnosis of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a disorder leading to pediatric pseudo-obstruction. MYLK, LMOD1, MYL9, and MYH11 encode for various proteins within smooth muscle cells; abnormalities within these proteins lead to abnormal intestinal smooth muscle contractions. Chronic intestinal pseudo-obstruction (CIPO) is defined by symptoms of bowel obstruction in the absence of a lumen-occluding lesion. CIPO is a heterogeneous group of disorders caused by abnormalities in the enteric neurons, intestinal smooth muscle, and/or the interstitial cells of Cajal (ICC). Symptoms can be non-specific and etiologies include both primary and secondary causes of CIPO that contribute to the delay in recognizing this condition and making the correct diagnosis. Chronic intestinal pseudo-obstruction has been recognized in both adults and children with fundamental differences in the etiology, symptom onset, clinical features and natural history of this disorder. For this reason, it has been considered a separate entity referred to as pediatric intestinal pseudo-obstruction (PIPO).
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Affiliation(s)
- Heidi E Gamboa
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
| | - Manu Sood
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA
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34
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Beaman GM, Galatà G, Teik KW, Urquhart JE, Aishah A, O'Sullivan J, Bhaskar SS, Wood KA, Thomas HB, O'Keefe RT, Woolf AS, Stuart HM, Newman WG. A homozygous missense variant in CHRM3 associated with familial urinary bladder disease. Clin Genet 2019; 96:515-520. [PMID: 31441039 PMCID: PMC6899476 DOI: 10.1111/cge.13631] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 07/19/2019] [Accepted: 08/02/2019] [Indexed: 12/13/2022]
Abstract
CHRM3 codes for the M3 muscarinic acetylcholine receptor that is located on the surface of smooth muscle cells of the detrusor, the muscle that effects urinary voiding. Previously, we reported brothers in a family affected by a congenital prune belly‐like syndrome with mydriasis due to homozygous CHRM3 frameshift variants. In this study, we describe two sisters with bladders that failed to empty completely and pupils that failed to constrict fully in response to light, who are homozygous for the missense CHRM3 variant c.352G > A; p.(Gly118Arg). Samples were not available for genotyping from their brother, who had a history of multiple urinary tract infections and underwent surgical bladder draining in the first year of life. He died at the age of 6 years. This is the first independent report of biallelic variants in CHRM3 in a family with a rare serious bladder disorder associated with mydriasis and provides important evidence of this association.
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Affiliation(s)
- Glenda M Beaman
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK
| | - Gabriella Galatà
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK
| | - Keng W Teik
- Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Jill E Urquhart
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK
| | - Ali Aishah
- Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - James O'Sullivan
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK
| | - Sanjeev S Bhaskar
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK
| | - Katherine A Wood
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK
| | - Huw B Thomas
- Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK
| | - Raymond T O'Keefe
- Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK
| | - Adrian S Woolf
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.,Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Helen M Stuart
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK
| | - William G Newman
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Human Sciences, University of Manchester, Manchester, UK.,Peking University Health Sciences Center, Beijing, China
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35
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Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family. J Hum Genet 2019; 64:1067-1073. [PMID: 31427716 PMCID: PMC6760584 DOI: 10.1038/s10038-019-0651-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 07/24/2019] [Accepted: 07/25/2019] [Indexed: 12/13/2022]
Abstract
Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a rare and severe disorder characterized by functional obstruction in the urinary and gastrointestinal tract. The molecular basis of this condition has been defined recently. Heterozygous variants in ACTG2, homozygous mutations in LMOD1, MYLK, and MYH9 were related to the pathogenesis of the syndrome, which encodes proteins involved in the process of smooth muscle contraction, supporting a myopathic basis for the disease. Recent studies have identified homozygous or compound heterozygous variants in MYH11 as a candidate gene of MMIHS. In this report, we described a nonconsanguineous Chinese family with three male fetuses affected with megacystis. Trio-targeted exome sequencing identified compound heterozygous variants, c.2051 G > A (p.R684H) and c.3540_3541delinsTT (p.(E1180D, Q1181Ter)), in MYH11 (NM_001040114). The variants were inherited from the parents, respectively. Western blotting showed a marked decrease in MYH11 protein in the proband's umbilical cord tissue compared with the control sample. The study's results confirmed that MYH11 is a candidate gene for MMIHS with autosomal recessive (AR) inheritance and expanded the mutation spectrum for this clinical condition. Combining clinical phenotype with molecular diagnosis may enable the identification of candidate genes for potential monogenic diseases and facilitate accurate genetic counseling, informed decision-making, and prenatal diagnosis.
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36
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Dong W, Baldwin C, Choi J, Milunsky JM, Zhang J, Bilguvar K, Lifton RP, Milunsky A. Identification of a dominant MYH11 causal variant in chronic intestinal pseudo-obstruction: Results of whole-exome sequencing. Clin Genet 2019; 96:473-477. [PMID: 31389005 DOI: 10.1111/cge.13617] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/26/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023]
Abstract
Chronic Intestinal Pseudo-Obstruction (CIPO) is a rare gastrointestinal disorder, which affects the smooth muscle contractions of the gastrointestinal tract. Dominant mutations in the smooth muscle actin gene, ACTG2, accounts for 44%-50% of CIPO patients. Other recessive or X-linked genes, including MYLK, LMOD1, RAD21, MYH11, MYL9, and FLNA were reported in single cases. In this study, we used Whole-Exome Sequencing (WES) to study 23 independent CIPO families including one extended family with 13 affected members. A dominantly inherited rare mutation, c.5819delC (p.Pro1940HisfsTer91), in the smooth muscle myosin gene, MYH11, was found in the extended family, shared by 7 affected family members but not by 3 unaffected family members with available DNA, suggesting a high probability of genetic linkage. Gene burden analysis indicates that additional genes, COL4A1, FBLN1 and HK2, may be associated with the disease. This study expanded our understanding of CIPO etiology and provided additional genetic evidence to physicians and genetic counselors for CIPO diagnosis.
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Affiliation(s)
- Weilai Dong
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
| | - Clinton Baldwin
- Center for Human Genetics and Dept. Ob/Gyn, Tufts University School of Medicine, Boston, Massachusetts
| | - Jungmin Choi
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.,Laboratory of Human Genetics and Genomics, Rockefeller University, New York, New York
| | - Jeff M Milunsky
- Center for Human Genetics and Dept. Ob/Gyn, Tufts University School of Medicine, Boston, Massachusetts
| | - Junhui Zhang
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
| | - Kaya Bilguvar
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
| | - Richard P Lifton
- Laboratory of Human Genetics and Genomics, Rockefeller University, New York, New York
| | - Aubrey Milunsky
- Center for Human Genetics and Dept. Ob/Gyn, Tufts University School of Medicine, Boston, Massachusetts
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37
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Kloth K, Renner S, Burmester G, Steinemann D, Pabst B, Lorenz B, Simon R, Kolbe V, Hempel M, Rosenberger G. 16p13.11 microdeletion uncovers loss‐of‐function of a
MYH11
missense variant in a patient with megacystis‐microcolon‐intestinal‐hypoperistalsis syndrome. Clin Genet 2019; 96:85-90. [DOI: 10.1111/cge.13557] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/18/2019] [Accepted: 04/28/2019] [Indexed: 12/19/2022]
Affiliation(s)
- Katja Kloth
- Institute of Human GeneticsUniversity Medical Center Hamburg‐Eppendorf Hamburg Germany
| | - Sina Renner
- Institute of Human GeneticsUniversity Medical Center Hamburg‐Eppendorf Hamburg Germany
| | - Gunter Burmester
- Department of PediatricsAltonaer Kinderkrankenhaus Hamburg Germany
| | - Doris Steinemann
- Department of Human GeneticsMedical Center Hannover Hannover Germany
| | - Brigitte Pabst
- Department of Human GeneticsMedical Center Hannover Hannover Germany
| | | | - Ronald Simon
- Institute of PathologyUniversity Medical Center Hamburg‐Eppendorf Hamburg Germany
| | - Verena Kolbe
- Institute of Human GeneticsUniversity Medical Center Hamburg‐Eppendorf Hamburg Germany
| | - Maja Hempel
- Institute of Human GeneticsUniversity Medical Center Hamburg‐Eppendorf Hamburg Germany
| | - Georg Rosenberger
- Institute of Human GeneticsUniversity Medical Center Hamburg‐Eppendorf Hamburg Germany
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38
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Eşsizoğlu P, Özlü F, Şimşek H, Yapıcıoğlu H, Satar M, Özden Ö. Bir yenidoğanda megasistis mikrokolon intestinal hipoperistaltizm sendromu. CUKUROVA MEDICAL JOURNAL 2019. [DOI: 10.17826/cumj.442232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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