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Wang F, Zou X, Zheng H, Kong T, Pei D. Human epicardial organoids from pluripotent stem cells resemble fetal stage with potential cardiomyocyte- transdifferentiation. Cell Biosci 2025; 15:4. [PMID: 39825425 PMCID: PMC11740338 DOI: 10.1186/s13578-024-01339-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 12/16/2024] [Indexed: 01/20/2025] Open
Abstract
Epicardium, the most outer mesothelium, exerts crucial functions in fetal heart development and adult heart regeneration. Here we use a three-step manipulation of WNT signalling entwined with BMP and RA signalling for generating a self-organized epicardial organoid that highly express with epicardium makers WT1 and TCF21 from human embryonic stem cells. After 8-days treatment of TGF-beta following by bFGF, cells enter into epithelium-mesenchymal transition and give rise to smooth muscle cells. Epicardium could also integrate and invade into mouse heart with SNAI1 expression, and give birth to numerous cardiomyocyte-like cells. Single-cell RNA seq unveils the heterogeneity and multipotency exhibited by epicardium-derived-cells and fetal-like epicardium. Meanwhile, extracellular matrix and growth factors secreted by epicardial organoid mimics the ecology of subepicardial space between the epicardium and cardiomyocytes. As such, this epicardial organoid offers a unique ground for investigating and exploring the potential of epicardium in heart development and regeneration.
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Affiliation(s)
- Fanwen Wang
- College of Life Sciences, Zhejiang University, Hangzhou, China
- Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China
| | - Xinle Zou
- Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China.
| | - Huilin Zheng
- Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China
- College of Biological & Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, China
| | - Tianci Kong
- College of Biological & Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, China
| | - Duanqing Pei
- Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China.
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
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Kocagil S, Susam E, Yimenicioğlu S, Aynaci S, Gökalp EE, Artan S. Interstitial 3p25.3 deletion syndrome: 13 years'-long follow-up of an affected individual. Clin Dysmorphol 2024; 33:183-186. [PMID: 38856647 DOI: 10.1097/mcd.0000000000000503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Affiliation(s)
- Sinem Kocagil
- Department of Medical Genetics, Eskisehir Osmangazi University, Eskisehir
| | - Ezgi Susam
- Department of Medical Genetics, Sakarya Training and Research Hospital, Sakarya
| | - Sevgi Yimenicioğlu
- Department of Pediatric Neurology, Eskisehir City Hospital, Eskisehir, Turkey
| | - Sabri Aynaci
- Department of Medical Genetics, Eskisehir Osmangazi University, Eskisehir
| | | | - Sevilhan Artan
- Department of Medical Genetics, Eskisehir Osmangazi University, Eskisehir
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Opris CE, Suciu H, Flamand S, Opris CI, Hamida AH, Gurzu S. Update on the genetic profile of mitral valve development and prolapse. Pathol Res Pract 2024; 262:155535. [PMID: 39182449 DOI: 10.1016/j.prp.2024.155535] [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: 06/17/2024] [Revised: 07/21/2024] [Accepted: 08/11/2024] [Indexed: 08/27/2024]
Abstract
The purpose of this review is to present a comprehensive overview of the literature published up to February 2024 on the PubMed database regarding the development of mitral valve disease, with detailed reference to mitral valve prolapse, from embryology to a genetic profile. Out of the 3291 publications that deal with mitral valve embryology, 215 refer to mitral valve genetics and 83 were selected for further analysis. After reviewing these data, we advocate for the importance of a gene-based therapy that should be available soon, to prevent or treat non-invasively the valvular degeneration.
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Affiliation(s)
- Carmen Elena Opris
- Department of Adult and Children Cardiovascular Recovery, Emergency Institute for Cardio-Vascular Diseases and Transplantation, Targu Mures 540139, Romania; Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, Targu Mures , Romania; Department of Cardiovascular Surgery, Emergency University Hospital, Romania
| | - Horatiu Suciu
- Department of Surgery, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures 540139, Romania; Romanian Academy of Medical Sciences, Romania; Department of Cardiovascular Surgery, Emergency University Hospital, Romania
| | - Sanziana Flamand
- Department of Surgery, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures 540139, Romania; Department of Cardiovascular Surgery, Emergency University Hospital, Romania
| | - Cosmin Ioan Opris
- Department of Surgery, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures 540139, Romania; Department of Cardiovascular Surgery, Emergency University Hospital, Romania
| | - Al Hussein Hamida
- Department of Surgery, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures 540139, Romania
| | - Simona Gurzu
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, Targu Mures , Romania; Romanian Academy of Medical Sciences, Romania; Research Center for Oncopathology and Translational Medicine (CCOMT), George Emil Palade University of Medicine, Pharmacy, Science and Technology, Targu Mures, Romania.
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Page ML, Aguzzoli Heberle B, Brandon JA, Wadsworth ME, Gordon LA, Nations KA, Ebbert MTW. Surveying the landscape of RNA isoform diversity and expression across 9 GTEx tissues using long-read sequencing data. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.13.579945. [PMID: 38405825 PMCID: PMC10888753 DOI: 10.1101/2024.02.13.579945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Even though alternative RNA splicing was discovered nearly 50 years ago (1977), we still understand very little about most isoforms arising from a single gene, including in which tissues they are expressed and if their functions differ. Human gene annotations suggest remarkable transcriptional complexity, with approximately 252,798 distinct RNA isoform annotations from 62,710 gene bodies (Ensembl v109; 2023), emphasizing the need to understand their biological effects. For example, 256 gene bodies have ≥50 annotated isoforms and 30 have ≥100, where one protein-coding gene (MAPK10) even has 192 distinct RNA isoform annotations. Whether such isoform diversity results from biological redundancy or spurious alternative splicing (i.e., noise), or whether individual isoforms have specialized functions (even if subtle) remains a mystery for most genes. Recent studies by Aguzzoli-Heberle et al., Leung et al., and Glinos et al. demonstrated long-read RNAseq enables improved RNA isoform quantification for essentially any tissue, cell type, or biological condition (e.g., disease, development, aging, etc.), making it possible to better assess individual isoform expression and function. While each study provided important discoveries related to RNA isoform diversity, deeper exploration is needed. We sought to quantify and characterize real isoform usage across tissues (compared to annotations). We used long-read RNAseq data from 58 GTEx samples across nine tissues (three brain, two heart, muscle, lung, liver, and cultured fibroblasts) generated by Glinos et al. and found considerable isoform diversity within and across tissues. Cerebellar hemisphere was the most transcriptionally complex tissue (22,522 distinct isoforms; 3,726 unique); liver was least diverse (12,435 distinct isoforms; 1,039 unique). We highlight gene clusters exhibiting high tissue-specific isoform diversity per tissue (e.g., TPM1 expresses 19 in heart's atrial appendage). We also validated 447 of the 700 new isoforms discovered by Aguzzoli-Heberle et al. and found that 88 were expressed in all nine tissues, while 58 were specific to a single tissue. This study represents a broad survey of the RNA isoform landscape, demonstrating isoform diversity across nine tissues and emphasizes the need to better understand how individual isoforms from a single gene body contribute to human health and disease.
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Affiliation(s)
- Madeline L. Page
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY
- Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY
| | - Bernardo Aguzzoli Heberle
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY
- Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY
| | - J. Anthony Brandon
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY
- Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY
| | - Mark E. Wadsworth
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY
- Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY
| | - Lacey A. Gordon
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY
- Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY
| | - Kayla A. Nations
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY
- Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY
| | - Mark T. W. Ebbert
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY
- Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY
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Parker LE, Karra R. Cardioprotective effects of the angiocrine CRELD2 after ischemic injury. NATURE CARDIOVASCULAR RESEARCH 2024; 3:104-105. [PMID: 39196187 DOI: 10.1038/s44161-023-00415-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Affiliation(s)
- Lauren E Parker
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Ravi Karra
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
- Department of Pathology, Duke University Medical Center, Durham, NC, USA.
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Jeffries L, Mis EK, McWalter K, Donkervoort S, Brodsky NN, Carpier JM, Ji W, Ionita C, Roy B, Morrow JS, Darbinyan A, Iyer K, Aul RB, Banka S, Chao KR, Cobbold L, Cohen S, Custodio HM, Drummond-Borg M, Elmslie F, Finanger E, Hainline BE, Helbig I, Hewson S, Hu Y, Jackson A, Josifova D, Konstantino M, Leach ME, Mak B, McCormick D, McGee E, Nelson S, Nguyen J, Nugent K, Ortega L, Goodkin HP, Roeder E, Roy S, Sapp K, Saade D, Sisodiya SM, Stals K, Towner S, Wilson W, Khokha MK, Bönnemann CG, Lucas CL, Lakhani SA. Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections. Genet Med 2024; 26:101023. [PMID: 37947183 PMCID: PMC10932913 DOI: 10.1016/j.gim.2023.101023] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 10/23/2023] [Accepted: 10/25/2023] [Indexed: 11/12/2023] Open
Abstract
PURPOSE We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants. METHODS The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells. RESULTS Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors. CONCLUSION This patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.
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Affiliation(s)
- Lauren Jeffries
- Yale University School of Medicine, Department of Pediatrics, New Haven, CT; Yale Pediatric Genomics Discovery Program, New Haven, CT
| | - Emily K Mis
- Yale University School of Medicine, Department of Pediatrics, New Haven, CT; Yale Pediatric Genomics Discovery Program, New Haven, CT
| | | | - Sandra Donkervoort
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Nina N Brodsky
- Yale University School of Medicine, Department of Pediatrics, New Haven, CT; Yale Pediatric Genomics Discovery Program, New Haven, CT; Yale University School of Medicine, Department of Immunobiology, New Haven, CT
| | - Jean-Marie Carpier
- Yale University School of Medicine, Department of Immunobiology, New Haven, CT
| | - Weizhen Ji
- Yale University School of Medicine, Department of Pediatrics, New Haven, CT; Yale Pediatric Genomics Discovery Program, New Haven, CT
| | - Cristian Ionita
- Yale University School of Medicine, Department of Pediatrics, New Haven, CT
| | - Bhaskar Roy
- Yale University School of Medicine, Department of Neurology, New Haven, CT
| | - Jon S Morrow
- Yale University School of Medicine, Department of Pathology, New Haven, CT
| | - Armine Darbinyan
- Yale University School of Medicine, Department of Pathology, New Haven, CT
| | - Krishna Iyer
- Yale University School of Medicine, Department of Pathology, New Haven, CT
| | - Ritu B Aul
- Hospital for Sick Children, Division of Clinical and Metabolic Genetics, Toronto, Ontario, Canada
| | - Siddharth Banka
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Katherine R Chao
- Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA
| | - Laura Cobbold
- South West Thames Regional Genetics Service, St George's, University of London, London, United Kingdom
| | - Stacey Cohen
- Children's Hospital of Philadelphia, Division of Neurology, Philadelphia, PA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA; University of Pennsylvania Perelman School of Medicine, Department of Neurology, Philadelphia, PA
| | - Helena M Custodio
- Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom; Chalfont Centre for Epilepsy, Buckinghamshire, United Kingdom
| | | | - Frances Elmslie
- South West Thames Regional Genetics Service, St George's, University of London, London, United Kingdom
| | | | - Bryan E Hainline
- Indiana University School of Medicine, Indiana University Health Physicians, Indianapolis, IN
| | - Ingo Helbig
- Children's Hospital of Philadelphia, Division of Neurology, Philadelphia, PA; University of Pennsylvania Perelman School of Medicine, Department of Neurology, Philadelphia, PA
| | - Stacy Hewson
- Hospital for Sick Children, Division of Clinical and Metabolic Genetics, Toronto, Ontario, Canada
| | - Ying Hu
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Adam Jackson
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Dragana Josifova
- Guys and St Thomas NHS Trust, Clinical Genetics, London, United Kingdom
| | | | | | - Bryan Mak
- University of California Los Angeles, David Geffen School of Medicine, Department of Human Genetics, Los Angeles, CA; Current affiliation: Genome Medical, South San Francisco, CA
| | - David McCormick
- King's College Hospital, Paediatric Neurosciences, London, United Kingdom
| | - Elisabeth McGee
- University of California Los Angeles, David Geffen School of Medicine, Department of Human Genetics, Los Angeles, CA; University of California Los Angeles, Clinical Genomics Center, Los Angeles, CA; University of California Los Angeles, Center for Duchenne Muscular Dystrophy, Los Angeles, CA
| | - Stanley Nelson
- University of California Los Angeles, David Geffen School of Medicine, Department of Human Genetics, Los Angeles, CA; University of California Los Angeles, Clinical Genomics Center, Los Angeles, CA; University of California Los Angeles, Center for Duchenne Muscular Dystrophy, Los Angeles, CA
| | - Joanne Nguyen
- Cook Children's Medical Center, Division of Genetics, Fort Worth, TX
| | - Kimberly Nugent
- Baylor College of Medicine, Department of Pediatrics, Houston, TX; Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX; Current affiliation: Cooper Surgical, Trumbull, CT
| | - Lucy Ortega
- Cook Children's Medical Center, Division of Genetics, Fort Worth, TX
| | | | - Elizabeth Roeder
- Baylor College of Medicine, Department of Pediatrics, Houston, TX; Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX
| | - Sani Roy
- Cook Children's Medical Center, Division of Endocrinology and Diabetes, Fort Worth, TX
| | - Katie Sapp
- Indiana University School of Medicine, Indiana University Health Physicians, Indianapolis, IN
| | - Dimah Saade
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Current affiliation: University of Iowa Carver College of Medicine, Iowa City, IA
| | - Sanjay M Sisodiya
- Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom; Chalfont Centre for Epilepsy, Buckinghamshire, United Kingdom
| | - Karen Stals
- Royal Devon & Exeter NHS Foundation Trust, Exeter Genomics Laboratory, Exeter, United Kingdom
| | - Shelley Towner
- University of Virginia School of Medicine, Charlottesville, VA
| | - William Wilson
- University of Virginia School of Medicine, Charlottesville, VA
| | - Mustafa K Khokha
- Yale University School of Medicine, Department of Pediatrics, New Haven, CT; Yale Pediatric Genomics Discovery Program, New Haven, CT; Yale University School of Medicine, Department of Genetics, New Haven, CT
| | - Carsten G Bönnemann
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Carrie L Lucas
- Yale Pediatric Genomics Discovery Program, New Haven, CT; Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Saquib A Lakhani
- Yale University School of Medicine, Department of Pediatrics, New Haven, CT; Yale Pediatric Genomics Discovery Program, New Haven, CT.
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Maslen CL. Human Genetics of Atrioventricular Septal Defect. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1441:559-571. [PMID: 38884732 DOI: 10.1007/978-3-031-44087-8_30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Atrioventricular septal defects (AVSD), also known as a common atrioventricular canal (CAVC), are clinically severe heart malformations that affect about 1 out of every 2100 live births. AVSD makes up about 5% of all congenital heart defects. AVSD is associated with cytogenetic disorders such as Down syndrome and numerous other rare genetic syndromes, but also occurs as a simplex trait. Studies in mouse models have identified over 100 genetic mutations that have the potential to cause an AVSD. However, studies in humans indicate that AVSD is genetically heterogeneous, and that the cause in humans is very rarely a single-gene defect. Familial cases do occur albeit rarely, usually with autosomal dominant inheritance and variable expression. In addition, the frequent occurrence of AVSD in some syndromes with known genetic causes such as heterotaxy syndrome points to additional genes/pathways that increase AVSD risk. Accordingly, while the genetic underpinnings for most AVSD remain unknown, there have been advances in identifying genetic risk factors for AVSD in both syndromic and nonsyndromic cases. This chapter summarizes the current knowledge of the genetic basis for AVSD.
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Affiliation(s)
- Cheryl L Maslen
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
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Perrot A, Rickert-Sperling S. Human Genetics of Defects of Situs. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1441:705-717. [PMID: 38884744 DOI: 10.1007/978-3-031-44087-8_42] [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: 06/18/2024]
Abstract
Defects of situs are associated with complex sets of congenital heart defects in which the normal concordance of asymmetric thoracic and abdominal organs is disturbed. The cellular and molecular mechanisms underlying the formation of the embryonic left-right axis have been investigated extensively in the past decade. This has led to the identification of mutations in at least 33 different genes in humans with heterotaxy and situs defects. Those mutations affect a broad range of molecular components, from transcription factors, signaling molecules, and chromatin modifiers to ciliary proteins. A substantial overlap of these genes is observed with genes associated with other congenital heart diseases such as tetralogy of Fallot and double-outlet right ventricle, d-transposition of the great arteries, and atrioventricular septal defects. In this chapter, we present the broad genetic heterogeneity of situs defects including recent human genomics efforts.
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Affiliation(s)
- Andreas Perrot
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin Berlin, Berlin, Germany
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Bolunduț AC, Lazea C, Mihu CM. Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects-A Narrative Review. CHILDREN (BASEL, SWITZERLAND) 2023; 10:children10050812. [PMID: 37238360 DOI: 10.3390/children10050812] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023]
Abstract
Congenital heart defects (CHD) are the most common congenital abnormality, with an overall global birth prevalence of 9.41 per 1000 live births. The etiology of CHDs is complex and still poorly understood. Environmental factors account for about 10% of all cases, while the rest are likely explained by a genetic component that is still under intense research. Transcription factors and signaling molecules are promising candidates for studies regarding the genetic burden of CHDs. The present narrative review provides an overview of the current knowledge regarding some of the genetic mechanisms involved in the embryological development of the cardiovascular system. In addition, we reviewed the association between the genetic variation in transcription factors and signaling molecules involved in heart development, including TBX5, GATA4, NKX2-5 and CRELD1, and congenital heart defects, providing insight into the complex pathogenesis of this heterogeneous group of diseases. Further research is needed in order to uncover their downstream targets and the complex network of interactions with non-genetic risk factors for a better molecular-phenotype correlation.
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Affiliation(s)
- Alexandru Cristian Bolunduț
- 1st Department of Pediatrics, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400370 Cluj-Napoca, Romania
| | - Cecilia Lazea
- 1st Department of Pediatrics, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400370 Cluj-Napoca, Romania
- 1st Pediatrics Clinic, Emergency Pediatric Hospital, 400370 Cluj-Napoca, Romania
| | - Carmen Mihaela Mihu
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
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10
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Pinnaro CT, Beck CB, Major HJ, Darbro BW. CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome. Hum Genet 2023; 142:523-530. [PMID: 36929416 PMCID: PMC10060348 DOI: 10.1007/s00439-023-02538-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/22/2023] [Indexed: 03/18/2023]
Abstract
Turner syndrome (TS) is a chromosomal disorder caused by complete or partial loss of the second sex chromosome and exhibits phenotypic heterogeneity, even after accounting for mosaicism and karyotypic variation. Congenital heart defects (CHD) are found in up to 45 percent of girls with TS and span a phenotypic continuum of obstructive left-sided lesions, with bicuspid aortic valve (BAV) being the most common. Several recent studies have demonstrated a genome-wide impact of X chromosome haploinsufficiency, including global hypomethylation and altered RNA expression. The presence of such broad changes to the TS epigenome and transcriptome led others to hypothesize that X chromosome haploinsufficiency sensitizes the TS genome, and several studies have demonstrated that a second genetic hit can modify disease susceptibility in TS. The objective of this study was to determine whether genetic variants in known heart developmental pathways act synergistically in this setting to increase the risk for CHD, specifically BAV, in TS. We analyzed 208 whole exomes from girls and women with TS and performed gene-based variant enrichment analysis and rare-variant association testing to identify variants associated with BAV in TS. Notably, rare variants in CRELD1 were significantly enriched in individuals with TS who had BAV compared to those with structurally normal hearts. CRELD1 is a protein that functions as a regulator of calcineurin/NFAT signaling, and rare variants in CRELD1 have been associated with both syndromic and non-syndromic CHD. This observation supports the hypothesis that genetic modifiers outside the X chromosome that lie in known heart development pathways may influence CHD risk in TS.
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Affiliation(s)
- Catherina T Pinnaro
- Stead Family Department of Pediatrics, University of Iowa, Iowa, IA, 52242, USA
| | - Chloe B Beck
- Stead Family Department of Pediatrics, University of Iowa, Iowa, IA, 52242, USA
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa, IA, 52242, USA
| | - Heather J Major
- Stead Family Department of Pediatrics, University of Iowa, Iowa, IA, 52242, USA
| | - Benjamin W Darbro
- Stead Family Department of Pediatrics, University of Iowa, Iowa, IA, 52242, USA.
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa, IA, 52242, USA.
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Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation. Int J Mol Sci 2023; 24:ijms24032918. [PMID: 36769235 PMCID: PMC9918028 DOI: 10.3390/ijms24032918] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 01/28/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Down syndrome (DS), a complex disorder that is caused by the trisomy of chromosome 21 (Hsa21), is a major cause of congenital heart defects (CHD). Interestingly, only about 50% of individuals with Hsa21 trisomy manifest CHD. Here we review the genetic basis of CHD in DS, focusing on genes that regulate extracellular matrix (ECM) organization. The overexpression of Hsa21 genes likely underlies the molecular mechanisms that contribute to CHD, even though the genes responsible for CHD could only be located in a critical region of Hsa21. A role in causing CHD has been attributed not only to protein-coding Hsa21 genes, but also to genes on other chromosomes, as well as miRNAs and lncRNAs. It is likely that the contribution of more than one gene is required, and that the overexpression of Hsa21 genes acts in combination with other genetic events, such as specific mutations or polymorphisms, amplifying their effect. Moreover, a key function in determining alterations in cardiac morphogenesis might be played by ECM. A large number of genes encoding ECM proteins are overexpressed in trisomic human fetal hearts, and many of them appear to be under the control of a Hsa21 gene, the RUNX1 transcription factor.
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Tang Q, Liu Q, Li Y, Mo L, He J. CRELD2, endoplasmic reticulum stress, and human diseases. Front Endocrinol (Lausanne) 2023; 14:1117414. [PMID: 36936176 PMCID: PMC10018036 DOI: 10.3389/fendo.2023.1117414] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/13/2023] [Indexed: 03/06/2023] Open
Abstract
CRELD2, a member of the cysteine-rich epidermal growth factor-like domain (CRELD) protein family, is both an endoplasmic reticulum (ER)-resident protein and a secretory factor. The expression and secretion of CRELD2 are dramatically induced by ER stress. CRELD2 is ubiquitously expressed in multiple tissues at different levels, suggesting its crucial and diverse roles in different tissues. Recent studies suggest that CRELD2 is associated with cartilage/bone metabolism homeostasis and pathological conditions involving ER stress such as chronic liver diseases, cardiovascular diseases, kidney diseases, and cancer. Herein, we first summarize ER stress and then critically review recent advances in the knowledge of the characteristics and functions of CRELD2 in various human diseases. Furthermore, we highlight challenges and present future directions to elucidate the roles of CRELD2 in human health and disease.
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Affiliation(s)
- Qin Tang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qinhui Liu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanping Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Li Mo
- Center of Gerontology and Geriatrics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhan He
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- *Correspondence: Jinhan He,
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Duxfield A, Munkley J, Briggs MD, Dennis EP. CRELD2 is a novel modulator of calcium release and calcineurin-NFAT signalling during osteoclast differentiation. Sci Rep 2022; 12:13884. [PMID: 35974042 PMCID: PMC9381524 DOI: 10.1038/s41598-022-17347-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 07/25/2022] [Indexed: 11/09/2022] Open
Abstract
Cysteine rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) is an endoplasmic reticulum (ER) resident chaperone protein with calcium binding properties. CRELD2 is an ER-stress regulated gene that has been implicated in the pathogenesis of skeletal dysplasias and has been shown to play an important role in the differentiation of chondrocytes and osteoblasts. Despite CRELD2 having an established role in skeletal development and bone formation, its role in osteoclasts is currently unknown. Here we show for the first time that CRELD2 plays a novel role in trafficking transforming growth factor beta 1 (TGF-β1), which is linked to an upregulation in the expression of Nfat2, the master regulator of osteoclast differentiation in early osteoclastogenesis. Despite this finding, we show that overexpressing CRELD2 impaired osteoclast differentiation due to a reduction in the activity of the calcium-dependant phosphatase, calcineurin. This in turn led to a subsequent block in the dephosphorylation of nuclear factor of activated T cells 1 (NFATc1), preventing its nuclear localisation and activation as a pro-osteoclastogenic transcription factor. Our exciting results show that the overexpression of Creld2 in osteoclasts impaired calcium release from the ER which is essential for activating calcineurin and promoting osteoclastogenesis. Therefore, our data proposes a novel inhibitory role for this calcium-binding ER-resident chaperone in modulating calcium flux during osteoclast differentiation which has important implications in our understanding of bone remodelling and the pathogenesis of skeletal diseases.
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Affiliation(s)
- Adam Duxfield
- International Centre for Life, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK
| | - Jennifer Munkley
- International Centre for Life, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK
| | - Michael D Briggs
- International Centre for Life, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK
| | - Ella P Dennis
- International Centre for Life, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
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Akalın M, Demirci O, Kumru P, Yücel İK. Heterotaxy syndrome: Prenatal diagnosis, concomitant malformations and outcomes. Prenat Diagn 2022; 42:435-446. [PMID: 35102577 DOI: 10.1002/pd.6110] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/15/2022] [Accepted: 01/27/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The aim of this study is to define cardiac and extracardiac malformations in fetuses with heterotaxy syndrome and to determine perinatal and childhood prognosis. METHODS In this retrospective study, fetuses diagnosed with heterotaxy syndrome on antenatal ultrasonography in a tertiary center between January 2014 and January 2021 were analyzed. Fetuses with heterotaxy syndrome were grouped as right atrial isomerism (RAI) and left atrial isomerism (LAI). RESULTS A total of 62 fetuses, 32 (51.6%) with RAI and 30 (48.4%) with LAI, were included in the study. Extracardiac anomaly was detected in 25% of fetuses with RAI and 44% of fetuses with LAI (p = 0.13). Patients with univentricular repair had a higher childhood mortality than patients with biventricular repair (p = 0.031). The presence of conotruncal anomaly was an independent factor affecting mortality (HR = 5.09, CI 95% 1.09-23.71, p = 0.039). CONCLUSION Hydrops fetalis, univentricular physiology and conotruncal anomalies are associated with poor outcomes in heterotaxy syndrome. The severity of the cardiac malformation is the main determinant of the outcomes. The presence of extracardiac malformations is associated with increased morbidity and mortality.
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Affiliation(s)
- Münip Akalın
- Department of Perinatology, University of Health Sciences Zeynep Kamil Women's and Children's Disease Training and Research Hospital, Istanbul, Turkey
| | - Oya Demirci
- Department of Perinatology, University of Health Sciences Zeynep Kamil Women's and Children's Disease Training and Research Hospital, Istanbul, Turkey
| | - Pınar Kumru
- Department of Obstetrics and Gynaecology, University of Health Sciences Zeynep Kamil Women's and Children's Disease Training and Research Hospital, Istanbul, Turkey
| | - İlker Kemal Yücel
- Department of Pediatric Cardiology, University of Health Sciences Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training & Research Hospital, Istanbul, Turkey
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Yadav ML, Ranjan P, Das P, Jain D, Kumar A, Mohapatra B. Implication of rare genetic variants of NODAL and ACVR1B in congenital heart disease patients from Indian population. Exp Cell Res 2021; 409:112869. [PMID: 34666056 DOI: 10.1016/j.yexcr.2021.112869] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 09/10/2021] [Accepted: 10/07/2021] [Indexed: 11/17/2022]
Abstract
NODAL signaling plays an essential role in vertebrate embryonic patterning and heart development. Accumulating evidences suggest that genetic mutations in TGF-β/NODAL signaling pathway can cause congenital heart disease in humans. To investigate the implication of NODAL signaling in isolated cardiovascular malformation, we have screened 300 non-syndromic CHD cases and 200 controls for NODAL and ACVR1B by Sanger sequencing and identified two rare missense (c.152C > T; p.P51L and c.981 T > A; p.D327E) variants in NODAL and a novel missense variant c.1035G > A; p.M345I in ACVR1B. All these variants are absent in 200 controls. Three-dimensional protein-modelling demonstrates that both p.P51L and p.D327E variations of NODAL and p.M345I mutation of ACVR1B, affect the tertiary structure of respective proteins. Variants of NODAL (p.P51L and p.D327E) and ACVR1B (p.M345I), significantly reduce the transactivation of AR3-Luc, (CAGA)12-Luc and (SBE)4-Luc promoters. Moreover, qRT-PCR results have also deciphered a reduction in the expression of cardiac-enriched transcription factors namely Gata4, Nkx2-5, and Tbx5 in both the mutants of NODAL. Decreased expression of, Gata4, Nkx2-5, Tbx5, and lefty is observed in p.M345I mutant of ACVR1B as well. Additionally, reduced phosphorylation of SMAD2/3 in response to these variants, suggests impaired NODAL signaling and possibly responsible for defective cell fate decision and differentiation of cardiomyocytes leading to CHD phenotype.
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Affiliation(s)
- Manohar Lal Yadav
- Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Prashant Ranjan
- Center of Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Parimal Das
- Center of Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Dharmendra Jain
- Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Ashok Kumar
- Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Bhagyalaxmi Mohapatra
- Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
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Harada N, Okamura Y, Kono T, Sakai M, Hikima JI. Identification of two interleukin 17 receptor C (IL-17RC) genes and their binding activities to three IL-17A/F ligands in the Japanese medaka, Oryzias latipes. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 124:104179. [PMID: 34171369 DOI: 10.1016/j.dci.2021.104179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/18/2021] [Accepted: 06/18/2021] [Indexed: 06/13/2023]
Abstract
In mammals, interleukin (IL)-17 receptor C (IL-17RC) and IL-17RA mediate IL-17A and IL-17F signaling to produce mucin, antimicrobial peptides, and maintain healthy intestinal flora. However, IL-17RC signaling in fish remains unclear. In this study, three il17rc transcripts (il17rca1, il17rca2, and il17rcb) from the Japanese medaka (Oryzias latipes) were cloned; il17rca1 and il17rca2 mRNAs were alternatively spliced from il17rca pre-mRNA as transcript variants. The il17rca and il17rcb genes were located on chromosomes 7 and 5, respectively. Teleost clades containing medaka il17rca and il17rcb clustered separately from the tetrapod clade. In adult tissues, il17rca1 expression was significantly higher than il17rca2 and il17rcb. Conversely, il17rcb expression was significantly higher in embryos and larvae. These expression patterns changed following infection with Edwardsiella piscicida and Aeromonas hydrophila. Furthermore, an immunoprecipitation assay using recombinant IL-17RCs and rIL-17A/Fs suggested that, in teleosts, three ligands could function in signaling through two IL-17RCs.
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Affiliation(s)
- Nanaki Harada
- International Course of Agriculture, Graduate School of Agriculture, University of Miyazaki, Miyazaki, 889-2192, Japan
| | - Yo Okamura
- Interdisciplinary Graduate School of Agriculture and Engineering, University of Miyazaki, Miyazaki, 889-2192, Japan
| | - Tomoya Kono
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, Miyazaki, 889-2192, Japan
| | - Masahiro Sakai
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, Miyazaki, 889-2192, Japan
| | - Jun-Ichi Hikima
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, Miyazaki, 889-2192, Japan.
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Chaklader M, Rothermel BA. Calcineurin in the heart: New horizons for an old friend. Cell Signal 2021; 87:110134. [PMID: 34454008 PMCID: PMC8908812 DOI: 10.1016/j.cellsig.2021.110134] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/10/2021] [Accepted: 08/23/2021] [Indexed: 01/20/2023]
Abstract
Calcineurin, also known as PP2B or PPP3, is a member of the PPP family of protein phosphatases that also includes PP1 and PP2A. Together these three phosphatases carryout the majority of dephosphorylation events in the heart. Calcineurin is distinct in that it is activated by the binding of calcium/calmodulin (Ca2+/CaM) and therefore acts as a node for integrating Ca2+ signals with changes in phosphorylation, two fundamental intracellular signaling cascades. In the heart, calcineurin is primarily thought of in the context of pathological cardiac remodeling, acting through the Nuclear Factor of Activated T-cell (NFAT) family of transcription factors. However, calcineurin activity is also essential for normal heart development and homeostasis in the adult heart. Furthermore, it is clear that NFAT-driven changes in transcription are not the only relevant processes initiated by calcineurin in the setting of pathological remodeling. There is a growing appreciation for the diversity of calcineurin substrates that can impact cardiac function as well as the diversity of mechanisms for targeting calcineurin to specific sub-cellular domains in cardiomyocytes and other cardiac cell types. Here, we will review the basics of calcineurin structure, regulation, and function in the context of cardiac biology. Particular attention will be given to: the development of improved tools to identify and validate new calcineurin substrates; recent studies identifying new calcineurin isoforms with unique properties and targeting mechanisms; and the role of calcineurin in cardiac development and regeneration.
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Affiliation(s)
- Malay Chaklader
- Departments of Internal Medicine (Division of Cardiology) and Molecular Biology, University of Texas Southwestern Medical Centre, Dallas, TX, USA
| | - Beverly A Rothermel
- Departments of Internal Medicine (Division of Cardiology) and Molecular Biology, University of Texas Southwestern Medical Centre, Dallas, TX, USA.
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Yasuhara J, Garg V. Genetics of congenital heart disease: a narrative review of recent advances and clinical implications. Transl Pediatr 2021; 10:2366-2386. [PMID: 34733677 PMCID: PMC8506053 DOI: 10.21037/tp-21-297] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/20/2021] [Indexed: 12/23/2022] Open
Abstract
Congenital heart disease (CHD) is the most common human birth defect and remains a leading cause of mortality in childhood. Although advances in clinical management have improved the survival of children with CHD, adult survivors commonly experience cardiac and non-cardiac comorbidities, which affect quality of life and prognosis. Therefore, the elucidation of genetic etiologies of CHD not only has important clinical implications for genetic counseling of patients and families but may also impact clinical outcomes by identifying at-risk patients. Recent advancements in genetic technologies, including massively parallel sequencing, have allowed for the discovery of new genetic etiologies for CHD. Although variant prioritization and interpretation of pathogenicity remain challenges in the field of CHD genomics, advances in single-cell genomics and functional genomics using cellular and animal models of CHD have the potential to provide novel insights into the underlying mechanisms of CHD and its associated morbidities. In this review, we provide an updated summary of the established genetic contributors to CHD and discuss recent advances in our understanding of the genetic architecture of CHD along with current challenges with the interpretation of genetic variation. Furthermore, we highlight the clinical implications of genetic findings to predict and potentially improve clinical outcomes in patients with CHD.
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Affiliation(s)
- Jun Yasuhara
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.,Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Vidu Garg
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.,Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA.,Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.,Department of Molecular Genetics, The Ohio State University, Columbus, Ohio, USA
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19
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Beckert V, Rassmann S, Kayvanjoo AH, Klausen C, Bonaguro L, Botermann DS, Krause M, Moreth K, Spielmann N, da Silva-Buttkus P, Fuchs H, Gailus-Durner V, de Angelis MH, Händler K, Ulas T, Aschenbrenner AC, Mass E, Wachten D. Creld1 regulates myocardial development and function. J Mol Cell Cardiol 2021; 156:45-56. [PMID: 33773996 DOI: 10.1016/j.yjmcc.2021.03.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 02/25/2021] [Accepted: 03/18/2021] [Indexed: 12/14/2022]
Abstract
CRELD1 (Cysteine-Rich with EGF-Like Domains 1) is a risk gene for non-syndromic atrioventricular septal defects in human patients. In a mouse model, Creld1 has been shown to be essential for heart development, particularly in septum and valve formation. However, due to the embryonic lethality of global Creld1 knockout (KO) mice, its cell type-specific function during peri- and postnatal stages remains unknown. Here, we generated conditional Creld1 KO mice lacking Creld1 either in the endocardium (KOTie2) or the myocardium (KOMyHC). Using a combination of cardiac phenotyping, histology, immunohistochemistry, RNA-sequencing, and flow cytometry, we demonstrate that Creld1 function in the endocardium is dispensable for heart development. Lack of myocardial Creld1 causes extracellular matrix remodeling and trabeculation defects by modulation of the Notch1 signaling pathway. Hence, KOMyHC mice die early postnatally due to myocardial hypoplasia. Our results reveal that Creld1 not only controls the formation of septa and valves at an early stage during heart development, but also cardiac maturation and function at a later stage. These findings underline the central role of Creld1 in mammalian heart development and function.
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Affiliation(s)
- Vera Beckert
- Institute of Innate Immunity, Biophysical Imaging, Medical Faculty, University of Bonn, 53127 Bonn, Germany
| | - Sebastian Rassmann
- Institute of Innate Immunity, Biophysical Imaging, Medical Faculty, University of Bonn, 53127 Bonn, Germany
| | - Amir Hossein Kayvanjoo
- Life & Medical Institute (LIMES), Developmental Biology of the Immune System, University of Bonn, 53115 Bonn, Germany
| | - Christina Klausen
- Institute of Innate Immunity, Biophysical Imaging, Medical Faculty, University of Bonn, 53127 Bonn, Germany
| | - Lorenzo Bonaguro
- Life & Medical Institute (LIMES), Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany
| | - Dominik Simon Botermann
- Institute of Innate Immunity, Biophysical Imaging, Medical Faculty, University of Bonn, 53127 Bonn, Germany
| | - Melanie Krause
- Institute of Innate Immunity, Biophysical Imaging, Medical Faculty, University of Bonn, 53127 Bonn, Germany
| | - Kristin Moreth
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Nadine Spielmann
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Patricia da Silva-Buttkus
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Helmut Fuchs
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Valerie Gailus-Durner
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany
| | - Martin Hrabě de Angelis
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technical University Munich, 85354 Freising, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Kristian Händler
- German Center for Neurodegenerative Diseases (DZNE), PRECISE Platform for Single Cell Genomics and Epigenomics at the DZNE and the University of Bonn, 53127 Bonn, Germany
| | - Thomas Ulas
- Life & Medical Institute (LIMES), Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), PRECISE Platform for Single Cell Genomics and Epigenomics at the DZNE and the University of Bonn, 53127 Bonn, Germany
| | - Anna C Aschenbrenner
- Life & Medical Institute (LIMES), Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500HB Nijmegen, the Netherlands
| | - Elvira Mass
- Life & Medical Institute (LIMES), Developmental Biology of the Immune System, University of Bonn, 53115 Bonn, Germany.
| | - Dagmar Wachten
- Institute of Innate Immunity, Biophysical Imaging, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
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Diz OM, Toro R, Cesar S, Gomez O, Sarquella-Brugada G, Campuzano O. Personalized Genetic Diagnosis of Congenital Heart Defects in Newborns. J Pers Med 2021; 11:562. [PMID: 34208491 PMCID: PMC8235407 DOI: 10.3390/jpm11060562] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/08/2021] [Accepted: 06/13/2021] [Indexed: 12/26/2022] Open
Abstract
Congenital heart disease is a group of pathologies characterized by structural malformations of the heart or great vessels. These alterations occur during the embryonic period and are the most frequently observed severe congenital malformations, the main cause of neonatal mortality due to malformation, and the second most frequent congenital malformations overall after malformations of the central nervous system. The severity of different types of congenital heart disease varies depending on the combination of associated anatomical defects. The causes of these malformations are usually considered multifactorial, but genetic variants play a key role. Currently, use of high-throughput genetic technologies allows identification of pathogenic aneuploidies, deletions/duplications of large segments, as well as rare single nucleotide variants. The high incidence of congenital heart disease as well as the associated complications makes it necessary to establish a diagnosis as early as possible to adopt the most appropriate measures in a personalized approach. In this review, we provide an exhaustive update of the genetic bases of the most frequent congenital heart diseases as well as other syndromes associated with congenital heart defects, and how genetic data can be translated to clinical practice in a personalized approach.
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Affiliation(s)
- Olga María Diz
- UGC Laboratorios, Hospital Universitario Puerta del Mar, 11009 Cadiz, Spain;
- Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08950 Barcelona, Spain
| | - Rocio Toro
- Medicine Department, School of Medicine, Cádiz University, 11519 Cadiz, Spain;
| | - Sergi Cesar
- Arrhythmia, Inherited Cardiac Diseases and Sudden Death Unit, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, University of Barcelona, 08007 Barcelona, Spain;
| | - Olga Gomez
- Fetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08950 Barcelona, Spain;
- Centre for Biomedical Research on Rare Diseases (CIBER-ER), 28029 Madrid, Spain
| | - Georgia Sarquella-Brugada
- Arrhythmia, Inherited Cardiac Diseases and Sudden Death Unit, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, University of Barcelona, 08007 Barcelona, Spain;
- Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain
| | - Oscar Campuzano
- Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08950 Barcelona, Spain
- Medical Science Department, School of Medicine, University of Girona, 17003 Girona, Spain
- Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBER-CV), 28029 Madrid, Spain
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21
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Redig JK, Fouad GT, Babcock D, Reshey B, Feingold E, Reeves RH, Maslen CL. Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects. AIMS GENETICS 2021. [DOI: 10.3934/genet.2014.1.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
AbstractAtrioventricular septal defects (AVSD) are highly heritable, clinically significant congenital heart malformations. Genetic and environmental modifiers of risk are thought to work in unknown combinations to cause AVSD. Approximately 5–10% of simplex AVSD cases carry a missense mutation in CRELD1. However, CRELD1 mutations are not fully penetrant and require interactions with other risk factors to result in AVSD. Vascular endothelial growth factor-A (VEGFA) is a well-characterized modulator of heart valve development. A functional VEGFA polymorphism, VEGFA c.−634C, which causes constitutively increased VEGFA expression, has been associated with cardiac septal defects suggesting it may be a genetic risk factor. To determine if there is an allelic association with AVSD we genotyped the VEGFA c.−634 SNP in a simplex AVSD study cohort. Over-representation of the c.−634C allele in the AVSD group suggested that this genotype may increase risk. Correlation of CRELD1 and VEGFA genotypes revealed that potentially pathogenic missense mutations in CRELD1 were always accompanied by the VEGFA c.−634C allele in individuals with AVSD suggesting a potentially pathogenic allelic interaction. We used a Creld1 knockout mouse model to determine the effect of deficiency of Creld1 combined with increased VEGFA on atrioventricular canal development. Morphogenic response to VEGFA was abnormal in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis. This supports our hypothesis that an additive effect between missense mutations in CRELD1 and a functional SNP in VEGFA contributes to the pathogenesis of AVSD.
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Affiliation(s)
- Jennifer K. Redig
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA
- Current address, Hume Center for Writing and Speaking, Stanford University, Stanford, CA 94305, USA
| | - Gameil T. Fouad
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA
- Current address, Biotron Laboratories, West Centerville, UT 84014, USA
| | - Darcie Babcock
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA
| | - Benjamin Reshey
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Eleanor Feingold
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh PA 15261, USA
| | - Roger H. Reeves
- Department of Physiology and the Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Cheryl L. Maslen
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA
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22
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Fetal Cystic Hygroma Associated with Terminal 2p25.1 Duplication and Terminal 3p25.3 Deletion: Cytogenetic, Fluorescent in Situ Hybridization and Microarray Familial Characterization of Two Different Chromosomal Structural Rearrangements. Balkan J Med Genet 2021; 23:79-86. [PMID: 33816076 PMCID: PMC8009571 DOI: 10.2478/bjmg-2020-0023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
We report a prenatally diagnosed case of partial trisomy 2p and partial monosomy 3p, resulting from unbalanced translocation (2;3)(p25.1;p25.3) of paternal origin. Parents were non consanguineous Caucasians, with familial history of recurrent miscarriages on the father’s side. Detailed sonographic examination of the fetus showed a septated cystic hygroma measuring 6 mm at 13 weeks’ gestation. Karyotyping and fluorescent in situ hybridization (FISH) analysis of cultured amniotic fluid cells revealed an unbalanced translocation der(3)t(2;3)(p25.1; p25.3) and apparently balanced inv(3)(p13p25.3) in a fetus. Parental cytogenetic evaluation using karyotyping and FISH analysis showed the presence of both a balanced translocation and a paracentric inversion in father t(2;3) (p25.1;p25.3) inv(3)(p13p25.3). Microarray analysis showed a 11.6 Mb deletion at 3p26.3-p25.3 and duplication of 10.5 Mb at the 2p25.3-p25 region. The duplicated region at 2p25.1p25.3 contains 45 different genes, where 12 are reported as OMIM morbid genes with different phenotypical implications. The deleted region at 3p26.3-p25.3 contains 65 genes, out of which 27 are OMIM genes. Three of these (CNTN4, SETD5 and VHL) were curated by Clingene Dosage Gene Map and were given a high haplo-insufficiency score. Genes affected by the unbalanced translocation could have contributed to some specific phenotypic changes of the fetus in late pregnancy. The application of different cytogenetic methods was essential in our case, allowing the detection of different types of structural chromosomal aberrations and more thorough genetic counseling for future pregnancies.
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23
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Nayak S, Kanakriyeh M, Varadarajan P. Echocardiographic assessment of atrioventricular canal defects. Echocardiography 2020; 37:2199-2210. [DOI: 10.1111/echo.14961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 11/28/2020] [Indexed: 11/30/2022] Open
Affiliation(s)
- Srishti Nayak
- Loma Linda University Medical Center Loma Linda CA USA
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24
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Chen H, Yang Z, Hou H, Wang J, Wang X, Yang Q, Liu L, He G. Novel mutations of TCTN3/LTBP2 with cellular function changes in congenital heart disease associated with polydactyly. J Cell Mol Med 2020; 24:13751-13762. [PMID: 33098376 PMCID: PMC7753982 DOI: 10.1111/jcmm.15950] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/21/2020] [Accepted: 08/27/2020] [Indexed: 12/20/2022] Open
Abstract
Congenital heart disease (CHD) associated with polydactyly involves various genes. We aimed to identify variations from genes related to complex CHD with polydactyly and to investigate the cellular functions related to the mutations. Blood was collected from a complex CHD case with polydactyly, and whole exome sequencing (WES) was performed. The CRISPR/Cas9 system was used to generate human pluripotent stem cell with mutations (hPSCs-Mut) that were differentiated into cardiomyocytes (hPSC-CMs-Mut) and analysed by transcriptomics on day 0, 9 and 13. Two heterozygous mutations, LTBP2 (c.2206G>A, p.Asp736Asn, RefSeq NM_000428.2) and TCTN3 (c.1268G>A, p.Gly423Glu, RefSeq NM_015631.5), were identified via WES but no TBX5 mutations were found. The stable cell lines of hPSCs-LTBP2mu /TCTN3mu were constructed and differentiated into hPSC-CMs-LTBP2mu /TCTN3mu . Compared to the wild type, LTBP2 mutation delayed the development of CMs. The TCTN3 mutation consistently presented lower rate and weaker force of the contraction of CMs. For gene expression pattern of persistent up-regulation, pathways in cardiac development and congenital heart disease were enriched in hPSCs-CM-LTBP2mu , compared with hPSCs-CM-WT. Thus, the heterozygous mutations in TCTN3 and LTBP2 affect contractility (rate and force) of cardiac myocytes and may affect the development of the heart. These findings provide new insights into the pathogenesis of complex CHD with polydactyly.
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Affiliation(s)
- Huan‐Xin Chen
- Center for Basic Medical Research & Department of Cardiovascular SurgeryTEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
| | - Zi‐Yue Yang
- College of Life SciencesNankai UniversityTianjinChina
| | - Hai‐Tao Hou
- Center for Basic Medical Research & Department of Cardiovascular SurgeryTEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
| | - Jun Wang
- Center for Basic Medical Research & Department of Cardiovascular SurgeryTEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
| | - Xiu‐Li Wang
- Center for Basic Medical Research & Department of Cardiovascular SurgeryTEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
| | - Qin Yang
- Center for Basic Medical Research & Department of Cardiovascular SurgeryTEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
| | - Lin Liu
- College of Life SciencesNankai UniversityTianjinChina
| | - Guo‐Wei He
- Center for Basic Medical Research & Department of Cardiovascular SurgeryTEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
- Zhejiang UniversityHangzhouZhejiangChina
- Drug Research and Development CenterWannan Medical CollegeWuhuAnhuiChina
- Department of SurgeryOregon Health and Science UniversityPortlandORUSA
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25
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CRELD1 modulates homeostasis of the immune system in mice and humans. Nat Immunol 2020; 21:1517-1527. [PMID: 33169013 DOI: 10.1038/s41590-020-00811-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 09/16/2020] [Indexed: 01/01/2023]
Abstract
CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic, functional and transcriptional differences, including reduced CD4+ T cell numbers. These findings were validated in T cell-specific Creld1-deficient mice. Loss of Creld1 was associated with simultaneous overactivation and increased apoptosis, resulting in a net loss of T cells with age. Creld1 was transcriptionally and functionally linked to Wnt signaling. Collectively, gene expression variance in large human cohorts combined with murine genetic models, transcriptomics and functional testing defines CRELD1 as an important modulator of immune homeostasis.
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26
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Dennis EP, Edwards SM, Jackson RM, Hartley CL, Tsompani D, Capulli M, Teti A, Boot-Handford RP, Young DA, Piróg KA, Briggs MD. CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development. J Bone Miner Res 2020; 35:1452-1469. [PMID: 32181934 DOI: 10.1002/jbmr.4010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/02/2020] [Accepted: 03/10/2020] [Indexed: 12/12/2022]
Abstract
Cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) is an endoplasmic reticulum (ER)-resident chaperone highly activated under ER stress in conditions such as chondrodysplasias; however, its role in healthy skeletal development is unknown. We show for the first time that cartilage-specific deletion of Creld2 results in disrupted endochondral ossification and short limbed dwarfism, whereas deletion of Creld2 in bone results in osteopenia, with a low bone density and altered trabecular architecture. Our study provides the first evidence that CRELD2 promotes the differentiation and maturation of skeletal cells by modulating noncanonical WNT4 signaling regulated by p38 MAPK. Furthermore, we show that CRELD2 is a novel chaperone for the receptor low-density lipoprotein receptor-related protein 1 (LRP1), promoting its transport to the cell surface, and that LRP1 directly regulates WNT4 expression in chondrocytes through TGF-β1 signaling. Therefore, our data provide a novel link between an ER-resident chaperone and the essential WNT signaling pathways active during skeletal differentiation that could be applicable in other WNT-responsive tissues. © 2020 American Society for Bone and Mineral Research. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
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Affiliation(s)
- Ella P Dennis
- Biosciences Institute, Newcastle University, International Centre for Life, Newcastle Upon Tyne, UK
| | - Sarah M Edwards
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
| | - Robert M Jackson
- Biosciences Institute, Newcastle University, International Centre for Life, Newcastle Upon Tyne, UK
| | - Claire L Hartley
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
| | - Dimitra Tsompani
- Biosciences Institute, Newcastle University, International Centre for Life, Newcastle Upon Tyne, UK
| | - Mattia Capulli
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Anna Teti
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | | | - David A Young
- Biosciences Institute, Newcastle University, International Centre for Life, Newcastle Upon Tyne, UK
| | - Katarzyna A Piróg
- Biosciences Institute, Newcastle University, International Centre for Life, Newcastle Upon Tyne, UK
| | - Michael D Briggs
- Biosciences Institute, Newcastle University, International Centre for Life, Newcastle Upon Tyne, UK
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27
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Pugnaloni F, Digilio MC, Putotto C, De Luca E, Marino B, Versacci P. Genetics of atrioventricular canal defects. Ital J Pediatr 2020; 46:61. [PMID: 32404184 PMCID: PMC7222302 DOI: 10.1186/s13052-020-00825-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 05/03/2020] [Indexed: 12/11/2022] Open
Abstract
Atrioventricular canal defect (AVCD) represents a quite common congenital heart defect (CHD) accounting for 7.4% of all cardiac malformations. AVCD is a very heterogeneous malformation that can occur as a phenotypical cardiac aspect in the context of different genetic syndromes but also as an isolated, non-syndromic cardiac defect. AVCD has also been described in several pedigrees suggesting a pattern of familiar recurrence. Targeted Next Generation Sequencing (NGS) techniques are proved to be a powerful tool to establish the molecular heterogeneity of AVCD. Given the complexity of cardiac embryology, it is not surprising that multiple genes deeply implicated in cardiogenesis have been described mutated in patients with AVCD. This review attempts to examine the recent advances in understanding the molecular basis of this complex CHD in the setting of genetic syndromes or in non-syndromic patients.
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Affiliation(s)
- Flaminia Pugnaloni
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Maria Cristina Digilio
- Medical Genetics Unit, Bambino Gesù Children's Hospital and Research Institute, 00165, Rome, Italy
| | - Carolina Putotto
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Enrica De Luca
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Bruno Marino
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Paolo Versacci
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy.
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28
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Kalayinia S, Maleki M, Mahdavi M, Mahdieh N. A novel de novo dominant mutation of NOTCH1 gene in an Iranian family with non-syndromic congenital heart disease. J Clin Lab Anal 2019; 34:e23147. [PMID: 31867804 PMCID: PMC7171333 DOI: 10.1002/jcla.23147] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/10/2019] [Accepted: 11/16/2019] [Indexed: 12/16/2022] Open
Abstract
Background Congenital heart disease (CHD) is the most common birth defect which can arises from different genetic defects. The genetic heterogeneity of this disease leads to restricted success in candidate genes screening method. Emerging approaches such as next‐generation sequencing (NGS)‐based genetic analysis might provide a better understating of CHD etiology in the patients who are left undiagnosed. To this aim, in this study, we survived the causes of CHD in an Iranian family who was consanguineous and had two affected children. Methods Affected individuals of this family were checked previously by PCR‐direct sequencing for six candidate genes (NKX2‐5, ZIC3, NODAL, FOXH1, GJA1, GATA4) and had not revealed any reported CHD causative mutations. Whole‐exome sequencing (WES) was performed on this family probond to determine the underlying cause of CHD, and the identified variants were confirmed and segregated by Sanger sequencing. Results We identified one heterozygous missense mutation, c.T6797C (p.Phe2266Ser), in the NOTCH1 gene, which seems to be the most probably disease causing of this family patients. This mutation was found to be novel and not reported on 1000 Genomes Project, dbSNP, and ExAC. Conclusion Worldwide, mutations in NOTCH1 gene are considered as one of the most known causes of CHD. The found NOTCH1 variant in this family affected individuals was the first report from Iran. Yet again, this result indicates the importance of NOTCH1 screening in CHD patients.
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Affiliation(s)
- Samira Kalayinia
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Maleki
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahdavi
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Nejat Mahdieh
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
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29
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Zhang H, Liu L, Tian J. Molecular mechanisms of congenital heart disease in down syndrome. Genes Dis 2019; 6:372-377. [PMID: 31832516 PMCID: PMC6889238 DOI: 10.1016/j.gendis.2019.06.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/17/2019] [Accepted: 06/27/2019] [Indexed: 12/31/2022] Open
Abstract
Down syndrome (DS), as a typical genomic aneuploidy, is a common cause of various birth defects, among which is congenital heart disease (CHD). 40-60% neonates with DS have some kinds of CHD. However, the molecular pathogenic mechanisms of DS associated CHD are still not fully understood. This review summarizes available studies on DS associated CHD from seven aspects so as to provide a crucial and updated overview of what we known so far in this domain.
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Affiliation(s)
- Hui Zhang
- Department of Cardiology, Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing 400014, China
| | - Lingjuan Liu
- Department of Cardiology, Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing 400014, China
| | - Jie Tian
- Department of Cardiology, Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing 400014, China
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30
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Yang RM, Tao J, Zhan M, Yuan H, Wang HH, Chen SJ, Chen Z, de Thé H, Zhou J, Guo Y, Zhu J. TAMM41 is required for heart valve differentiation via regulation of PINK-PARK2 dependent mitophagy. Cell Death Differ 2019; 26:2430-2446. [PMID: 30824836 PMCID: PMC6888875 DOI: 10.1038/s41418-019-0311-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 02/02/2019] [Accepted: 02/14/2019] [Indexed: 12/13/2022] Open
Abstract
TAMM41, located within the congenital heart diseases (CHD) sensitive region of 3p25 deletion syndrome, is a mitochondrial membrane maintenance protein critical for yeast survival, but its function in higher vertebrates remains unknown. Via in vivo zebrafish model, we found that tamm41 is highly expressed in the developing heart and deficiency of which led to heart valve abnormalities. Molecular mechanistic studies revealed that TAMM41 interacts and modulates the PINK1-PARK2 dependent mitophagy pathway, thereby implicating TAMM41 in heart valve development during zebrafish embryonic cardiogenesis. Furthermore, through screening of the congenital heart diseases (CHD) sensitive region of 3p25 deletion syndrome among 118 sporadic atrioventricular septal defect (AVSD) patients, we identified three cases carrying heterozygous pathogenic intronic variants of TAMM41. All three cases lacked normal full-length TAMM41 transcripts, most likely due to specific expression of the mutant allele. Collectively, our studies highlight essential roles for TAMM41-dependent mitophagy in development of the heart and provide novel insights into the etiology of AVSD.
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Affiliation(s)
- Rui Meng Yang
- CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jiong Tao
- Prenatal Diagnosis Center, Shanghai Jiao Tong University Affiliated First People's Hospital, 650 Xin song jiang Road, Shanghai, 201620, China
| | - Ming Zhan
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Hao Yuan
- CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Hai Hong Wang
- CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Sai Juan Chen
- CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhu Chen
- CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Hugues de Thé
- CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Université de Paris 7/INSERM/CNRS UMR 944/7212, Equipe Labellisée No. 11 Ligue Nationale Contre le Cancer, Hôpital St. Louis, Paris, France
| | - Jun Zhou
- CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ying Guo
- Department of Cardiology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
| | - Jun Zhu
- CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. .,Université de Paris 7/INSERM/CNRS UMR 944/7212, Equipe Labellisée No. 11 Ligue Nationale Contre le Cancer, Hôpital St. Louis, Paris, France.
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31
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The roles of MTRR and MTHFR gene polymorphisms in congenital heart diseases: a meta-analysis. Biosci Rep 2018; 38:BSR20181160. [PMID: 30333252 PMCID: PMC6435561 DOI: 10.1042/bsr20181160] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 08/14/2018] [Accepted: 09/06/2018] [Indexed: 12/13/2022] Open
Abstract
Background: We performed the present study to better elucidate the correlations of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms with the risk of congenital heart diseases (CHD). Methods: Eligible articles were searched in PubMed, Medline, Embase and CNKI. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations of MTHFR and MTRR gene polymorphisms with CHD. Results: A total of 47 eligible studies were finally included in our meta-analysis. Our overall analyses suggested that MTRR rs1801394, MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms were all significantly associated with the risk of CHD in certain genetic models. Further subgroup analyses according to ethnicity of study participants demonstrated that the MTRR rs1801394 polymorphism was significantly correlated with the risk of CHD only in Asians, whereas MTRR rs1532268, MTHFR rs1801133 and MTHFR rs1801131 polymorphisms were significantly correlated with the risk of CHD in both Asians and Caucasians. Conclusions: Our findings indicated that MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms may affect the risk of CHD in Asians and Caucasians, while the MTRR rs1801394 polymorphism may only affect in risk of CHD in Asians.
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32
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Wang W, Xu A, Xu H. The roles of vascular endothelial growth factor gene polymorphisms in congenital heart diseases: a meta-analysis. Growth Factors 2018; 36:232-238. [PMID: 30689460 DOI: 10.1080/08977194.2018.1513505] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
We performed this study to better elucidate the correlations between vascular endothelial growth factor (VEGF) gene polymorphisms and congenital heart diseases (CHD). Eligible articles were searched in PubMed, Medline, Embase and CNKI. Eighteen studies were finally included in our meta-analysis. A significant association with the risk of CHD was detected for the rs1570360 polymorphism in additive comparison in overall analyses. Further subgroup analyses according to ethnicity of study participants and type of disease demonstrated that the rs833061 polymorphism was significantly correlated with the risk of CHD in Asians under additive genetic model, and the rs3025039 polymorphism was significantly correlated with the risk of Tetralogy of Fallot (TOF) in dominant, recessive and allele models. In conclusion, our findings indicated that rs1570360 and rs833061 polymorphisms may affect the risk of CHD. In addition, the rs3025039 polymorphism may serve as a genetic biomarker of TOF.
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Affiliation(s)
- Weiping Wang
- a Department of Pediatrics , Changyi People's Hospital , Changyi , China
| | - Aiping Xu
- a Department of Pediatrics , Changyi People's Hospital , Changyi , China
| | - Hong Xu
- a Department of Pediatrics , Changyi People's Hospital , Changyi , China
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33
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Pierpont ME, Brueckner M, Chung WK, Garg V, Lacro RV, McGuire AL, Mital S, Priest JR, Pu WT, Roberts A, Ware SM, Gelb BD, Russell MW. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association. Circulation 2018; 138:e653-e711. [PMID: 30571578 PMCID: PMC6555769 DOI: 10.1161/cir.0000000000000606] [Citation(s) in RCA: 392] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.
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34
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D'Alessandro M, Richard M, Stigloher C, Gache V, Boulin T, Richmond JE, Bessereau JL. CRELD1 is an evolutionarily-conserved maturational enhancer of ionotropic acetylcholine receptors. eLife 2018; 7:39649. [PMID: 30407909 PMCID: PMC6245729 DOI: 10.7554/elife.39649] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 11/05/2018] [Indexed: 12/22/2022] Open
Abstract
The assembly of neurotransmitter receptors in the endoplasmic reticulum limits the number of receptors delivered to the plasma membrane, ultimately controlling neurotransmitter sensitivity and synaptic transfer function. In a forward genetic screen conducted in the nematode C. elegans, we identified crld-1 as a gene required for the synaptic expression of ionotropic acetylcholine receptors (AChR). We demonstrated that the CRLD-1A isoform is a membrane-associated ER-resident protein disulfide isomerase (PDI). It physically interacts with AChRs and promotes the assembly of AChR subunits in the ER. Mutations of Creld1, the human ortholog of crld-1a, are responsible for developmental cardiac defects. We showed that Creld1 knockdown in mouse muscle cells decreased surface expression of AChRs and that expression of mouse Creld1 in C. elegans rescued crld-1a mutant phenotypes. Altogether these results identify a novel and evolutionarily-conserved maturational enhancer of AChR biogenesis, which controls the abundance of functional receptors at the cell surface.
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Affiliation(s)
- Manuela D'Alessandro
- Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGène, Lyon, France
| | - Magali Richard
- Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGène, Lyon, France
| | - Christian Stigloher
- Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGène, Lyon, France
| | - Vincent Gache
- Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGène, Lyon, France
| | - Thomas Boulin
- Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGène, Lyon, France
| | - Janet E Richmond
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, United States
| | - Jean-Louis Bessereau
- Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGène, Lyon, France
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35
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A novel ZIC3 gene mutation identified in patients with heterotaxy and congenital heart disease. Sci Rep 2018; 8:12386. [PMID: 30120289 PMCID: PMC6098004 DOI: 10.1038/s41598-018-30204-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 07/19/2018] [Indexed: 12/12/2022] Open
Abstract
Heterotaxy syndrome (HTX) is characterized by left-right (LR) asymmetry disturbances associated with severe heart malformations. However, the exact genetic cause of HTX pathogenesis remains unclear. The aim of this study was to investigate the pathogenic mechanism underlying heterotaxy syndrome. Targeted next-generation sequencing (NGS) was performed for twenty-two candidate genes correlated with LR axis development in sixty-six HTX patients from unrelated families. Variants were filtered from databases and predicted in silico using prediction programs. A total of twenty-one potential disease-causing variants were identified in seven genes. Next, we used Sanger sequencing to confirm the identified variants in the family pedigree and found a novel hemizygous mutation (c.890G > T, p.C297F) in the ZIC3 gene in a male patient that was inherited from his mother, who was a carrier. The results of functional indicated that this ZIC3 mutation decreases transcriptional activity, affects the affinity of the GLI-binding site and results in aberrant cellular localization in transfected cells. Moreover, morpholino-knockdown experiments in zebrafish demonstrated that zic3 mutant mRNA failed to rescue the abnormal phenotype, suggesting a role for the novel ZIC3 mutation in heterotaxy syndrome.
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36
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Ferese R, Bonetti M, Consoli F, Guida V, Sarkozy A, Lepri FR, Versacci P, Gambardella S, Calcagni G, Margiotti K, Piceci Sparascio F, Hozhabri H, Mazza T, Digilio MC, Dallapiccola B, Tartaglia M, Marino B, Hertog JD, De Luca A. Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect. Hum Mutat 2018; 39:1428-1441. [PMID: 30007050 DOI: 10.1002/humu.23593] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 06/27/2018] [Accepted: 07/08/2018] [Indexed: 11/10/2022]
Abstract
Atrioventricular septal defect (AVSD) may occur as part of a complex disorder (e.g., Down syndrome, heterotaxy), or as isolate cardiac defect. Multiple lines of evidence support a role of calcineurin/NFAT signaling in AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT signaling have been reported in a small fraction of affected subjects. In this study, 22 patients with isolated AVSD and 38 with AVSD and heterotaxy were screened for NFATC1 gene mutations. Sequence analysis identified three missense variants in three individuals, including a subject with isolated AVSD [p.(Ala367Val)], an individual with AVSD and heterotaxy [p.(Val210Met)], and a subject with AVSD, heterotaxy, and oculo-auriculo-vertebral spectrum (OAVS) [p.(Ala696Thr)], respectively. The latter was also heterozygous for a missense change in TBX1 [p.(Pro86Leu)]. Targeted resequencing of genes associated with AVSD, heterotaxy, or OAVS excluded additional hits in the three mutation-positive subjects. Functional characterization of NFATC1 mutants documented defective nuclear translocation and decreased transcriptional transactivation activity. When expressed in zebrafish, the three NFATC1 mutants caused cardiac looping defects and altered atrioventricular canal patterning, providing evidence of their functional relevance in vivo. Our findings support a role of defective NFATC1 function in the etiology of isolated and heterotaxy-related AVSD.
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Affiliation(s)
| | - Monica Bonetti
- Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584CT, Utrecht, The Netherlands
| | - Federica Consoli
- Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy
| | - Valentina Guida
- Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy
| | - Anna Sarkozy
- Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy
| | - Francesca Romana Lepri
- Genetics and Rare Diseases Research Division, Bambino Gesù Children Hospital, IRCCS, 00146, Rome, Italy
| | - Paolo Versacci
- Division of Pediatric Cardiology, Department of Pediatrics, "Sapienza" University, 00161, Rome, Italy
| | | | - Giulio Calcagni
- Genetics and Rare Diseases Research Division, Bambino Gesù Children Hospital, IRCCS, 00146, Rome, Italy
| | - Katia Margiotti
- Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy
| | - Francesca Piceci Sparascio
- Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy
| | - Hossein Hozhabri
- Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy.,Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - Tommaso Mazza
- Bioinformatics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy
| | - Maria Cristina Digilio
- Genetics and Rare Diseases Research Division, Bambino Gesù Children Hospital, IRCCS, 00146, Rome, Italy
| | - Bruno Dallapiccola
- Genetics and Rare Diseases Research Division, Bambino Gesù Children Hospital, IRCCS, 00146, Rome, Italy
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Bambino Gesù Children Hospital, IRCCS, 00146, Rome, Italy
| | - Bruno Marino
- Division of Pediatric Cardiology, Department of Pediatrics, "Sapienza" University, 00161, Rome, Italy
| | - Jeroen den Hertog
- Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584CT, Utrecht, The Netherlands.,Institute of Biology, 2300RC, Leiden, The Netherlands
| | - Alessandro De Luca
- Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013, San Giovanni Rotondo, Italy
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Blue GM, Ip E, Walker K, Kirk EP, Loughran-Fowlds A, Sholler GF, Dunwoodie SL, Harvey RP, Giannoulatou E, Badawi N, Winlaw DS. Genetic burden and associations with adverse neurodevelopment in neonates with congenital heart disease. Am Heart J 2018; 201:33-39. [PMID: 29910053 DOI: 10.1016/j.ahj.2018.03.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 03/28/2018] [Indexed: 01/21/2023]
Abstract
BACKGROUND Up to 20% of children with congenital heart disease (CHD) undergoing cardiac surgery develop neurodevelopmental disabilities (NDD), with some studies reporting persistent impairment. Recent large-scale studies have demonstrated shared genetic mechanisms contributing to CHD and NDD. In this study, a targeted approach was applied to assess direct clinical applicability of this information. METHODS A gene panel comprising 148 known CHD and/or NDD genes was used to sequence 15 patients with CHD + NDD, 15 patients with CHD, and 15 healthy controls. The number and types of variants between the 3 groups were compared using Poisson log-linear regression, and the SNP-set (Sequence) Kernel Association Test-Optimized was used to conduct single-gene and gene-pathway burden analyses. RESULTS A significant increase in rare (minor allele frequency < 0.01) and novel variants was identified between the CHD + NDD cohort and controls, P < .001 and P = .001, respectively. There was also a significant increase in rare variants in the CHD cohort compared with controls (P = .04). Rare variant burden analyses implicated pathways associated with "neurotransmitters," "axon guidance," and those incorporating "RASopathy" genes in the development of NDD in CHD patients. CONCLUSIONS These findings suggest that an increase in novel and rare variants in known CHD and/or NDD genes is associated with the development of NDD in patients with CHD. Furthermore, burden analyses point toward rare variant burden specifically in pathways related to brain development and function as contributors to NDD. Although promising variants and pathways were identified, further research, utilizing whole-genome approaches, is required prior to demonstrating clinical utility in this patient group.
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Affiliation(s)
- Gillian M Blue
- Kids Heart Research, The Children's Hospital at Westmead, Sydney, Australia; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia
| | - Eddie Ip
- Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia
| | - Karen Walker
- Sydney Medical School, University of Sydney, Sydney, Australia; Grace Centre for Newborn Care, The Children's Hospital at Westmead, Sydney, Australia; Cerebral Palsy Alliance Research Institute, Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia
| | - Edwin P Kirk
- Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia; School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Alison Loughran-Fowlds
- Sydney Medical School, University of Sydney, Sydney, Australia; Grace Centre for Newborn Care, The Children's Hospital at Westmead, Sydney, Australia
| | - Gary F Sholler
- Kids Heart Research, The Children's Hospital at Westmead, Sydney, Australia; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia
| | - Sally L Dunwoodie
- Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Richard P Harvey
- Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, Sydney, Australia
| | - Eleni Giannoulatou
- Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Nadia Badawi
- Sydney Medical School, University of Sydney, Sydney, Australia; Grace Centre for Newborn Care, The Children's Hospital at Westmead, Sydney, Australia; Cerebral Palsy Alliance Research Institute, Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia
| | - David S Winlaw
- Kids Heart Research, The Children's Hospital at Westmead, Sydney, Australia; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia.
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Rambo-Martin BL, Mulle JG, Cutler DJ, Bean LJH, Rosser TC, Dooley KJ, Cua C, Capone G, Maslen CL, Reeves RH, Sherman SL, Zwick ME. Analysis of Copy Number Variants on Chromosome 21 in Down Syndrome-Associated Congenital Heart Defects. G3 (BETHESDA, MD.) 2018; 8:105-111. [PMID: 29141989 PMCID: PMC5765339 DOI: 10.1534/g3.117.300366] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 10/31/2017] [Indexed: 11/18/2022]
Abstract
One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: (1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and (2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 198 case individuals with DS+AVSD, and 211 control individuals with DS and a normal heart, using a custom microarray with dense probes tiled on chromosome 21 for array CGH (aCGH). We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. We also showed that previously DS+AVSD (DS and a complete AVSD)-associated common CNVs on chromosome 21 failed to replicate. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population.
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Affiliation(s)
| | - Jennifer G Mulle
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322
| | - David J Cutler
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Lora J H Bean
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Tracie C Rosser
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Kenneth J Dooley
- Department of Pediatrics, Sibley Heart Center Cardiology, Children's Healthcare of Atlanta, Atlanta, Georgia 30033
| | - Clifford Cua
- Heart Center, Nationwide Children's Hospital, Columbus, Ohio 43205
| | - George Capone
- Kennedy Krieger Institute, Baltimore, Maryland 21205
| | - Cheryl L Maslen
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon 97239
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon 97239
| | - Roger H Reeves
- Department of Physiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205
- McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205
| | - Stephanie L Sherman
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Michael E Zwick
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322
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39
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Asim A, Agarwal S, Panigrahi I, Sarangi AN, Muthuswamy S, Kapoor A. CRELD1 gene variants and atrioventricular septal defects in Down syndrome. Gene 2018; 641:180-185. [DOI: 10.1016/j.gene.2017.10.044] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 09/21/2017] [Accepted: 10/16/2017] [Indexed: 10/18/2022]
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40
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Diogenes TCP, Mourato FA, de Lima Filho JL, Mattos SDS. Gender differences in the prevalence of congenital heart disease in Down's syndrome: a brief meta-analysis. BMC MEDICAL GENETICS 2017; 18:111. [PMID: 28985718 PMCID: PMC6389118 DOI: 10.1186/s12881-017-0475-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 10/03/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Down's syndrome (DS) affects one per 700 live births and congenital heart disease (CHD) occurs in 40-60% of these patients. Contributing factors to the association between DS and CHD are being unraveled. Gender could be one of them. METHODS We performed a meta-analysis of CHD prevalence in DS, separated by gender. Three search engines were used and 578 articles were reviewed. Twelve articles were included. RESULTS Quantitative analysis showed a higher prevalence of CHD, particularly atrioventricular septal defects (AVSD), in female patients. No differences were found in others forms of CHD. CONCLUSION CHD, particularly AVSD, are more common in the female gender of Down's syndrome patients.
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Affiliation(s)
| | - Felipe Alves Mourato
- Círculo do Coração de Pernambuco, Recife, Pernambuco, Brazil. .,Universidade Federal de Pernambuco (UFPE), Recife, Pernambuco, Brazil. .,Unidade de Cardiologia Materno e Fetal (UCMF), Av. Governador Agamenon Magalhães, 4760, Paissandu, PE, CEP 52010-902, Brazil.
| | | | - Sandra da Silva Mattos
- Círculo do Coração de Pernambuco, Recife, Pernambuco, Brazil.,Universidade Federal de Pernambuco (UFPE), Recife, Pernambuco, Brazil
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41
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Plaiasu V. Down Syndrome - Genetics and Cardiogenetics. MAEDICA 2017; 12:208-213. [PMID: 29218069 PMCID: PMC5706761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
During the last years, Down syndrome has been the focus of special attention. Down syndrome is a genetic disorder characterized by distinct physical features and some degree of cognitive disability. Patients with Down syndrome also present many other congenital anomalies. The mapping for phenotypes to specific regions of chromosome 21 permits to identify which genes (or small regions) contribute to the phenotypic features of Down syndrome and thus, to understand its pathogenesis. Mainly there are three cytogenetic forms of Down syndrome: free trisomy 21, mosaic trisomy 21 and robertsonian translocation trisomy 21. Prenatal and postnatal testing has become commonly used to diagnose different cases presenting the same pathology. Early clinical diagnosis is extremely important for patient prognosis. Lately, advances in Down syndrome research have been registered, but little is known about cardiovascular phenotype in Down syndrome. About half of patients with Down syndrome have congenital heart disease, and atrioventricular septal defects are the most common defects found. Basic research on Down syndrome is now rapidly accelerating, using new genomic technologies. There were many studies performed to identify a correlation between genotype and phenotype in Down syndrome.
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Affiliation(s)
- Vasilica Plaiasu
- Alessandrescu-Rusescu INSMC, Regional Center of Medical Genetics, Bucharest, Romania
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42
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Catana A, Apostu AP. The determination factors of left-right asymmetry disorders- a short review. ACTA ACUST UNITED AC 2017; 90:139-146. [PMID: 28559696 PMCID: PMC5433564 DOI: 10.15386/cjmed-701] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 10/02/2016] [Accepted: 11/23/2016] [Indexed: 12/17/2022]
Abstract
Laterality defects in humans, situs inversus and heterotaxy, are rare disorders, with an incidence of 1:8000 to 1:10 000 in the general population, and a multifactorial etiology. It has been proved that 1.44/10 000 of all cardiac problems are associated with malformations of left-right asymmetry and heterotaxy accounts for 3% of all congenital heart defects. It is considered that defects of situs appear due to genetic and environmental factors. Also, there is evidence that the ciliopathies (defects of structure or function) are involved in development abnormalities. Over 100 genes have been reported to be involved in left-right patterning in model organisms, but only a few are likely to candidate for left-right asymmetry defects in humans. Left-right asymmetry disorders are genetically heterogeneous and have variable manifestations (from asymptomatic to serious clinical problems). The discovery of the right mechanism of left-right development will help explain the clinical complexity and may contribute to a therapy of these disorders.
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Affiliation(s)
- Andreea Catana
- Genetics Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Adina Patricia Apostu
- Genetics Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Abstract
Twenty years ago, chromosomal abnormalities were the only identifiable genetic causes of a small fraction of congenital heart defects (CHD). Today, a de novo or inherited genetic abnormality can be identified as pathogenic in one-third of cases. We refer to them here as monogenic causes, insofar as the genetic abnormality has a readily detectable, large effect. What explains the other two-thirds? This review considers a complex genetic basis. That is, a combination of genetic mutations or variants that individually may have little or no detectable effect contribute to the pathogenesis of a heart defect. Genes in the embryo that act directly in cardiac developmental pathways have received the most attention, but genes in the mother that establish the gestational milieu via pathways related to metabolism and aging also have an effect. A growing body of evidence highlights the pathogenic significance of genetic interactions in the embryo and maternal effects that have a genetic basis. The investigation of CHD as guided by a complex genetic model could help estimate risk more precisely and logically lead to a means of prevention.
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Affiliation(s)
- Ehiole Akhirome
- Department of Pediatrics, Washington University School of Medicine
| | - Nephi A Walton
- Department of Pediatrics, Washington University School of Medicine
| | - Julie M Nogee
- Department of Pediatrics, Washington University School of Medicine
| | - Patrick Y Jay
- Department of Pediatrics, Washington University School of Medicine
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44
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Jay PY, Akhirome E, Magnan RA, Zhang MR, Kang L, Qin Y, Ugwu N, Regmi SD, Nogee JM, Cheverud JM. Transgenerational cardiology: One way to a baby's heart is through the mother. Mol Cell Endocrinol 2016; 435:94-102. [PMID: 27555292 PMCID: PMC5014674 DOI: 10.1016/j.mce.2016.08.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 08/18/2016] [Accepted: 08/18/2016] [Indexed: 12/17/2022]
Abstract
Despite decades of progress, congenital heart disease remains a major cause of mortality and suffering in children and young adults. Prevention would be ideal, but formidable biological and technical hurdles face any intervention that seeks to target the main causes, genetic mutations in the embryo. Other factors, however, significantly modify the total risk in individuals who carry mutations. Investigation of these factors could lead to an alternative approach to prevention. To define the risk modifiers, our group has taken an "experimental epidemiologic" approach via inbred mouse strain crosses. The original intent was to map genes that modify an individual's risk of heart defects caused by an Nkx2-5 mutation. During the analysis of >2000 Nkx2-5(+/-) offspring from one cross we serendipitously discovered a maternal-age associated risk, which also exists in humans. Reciprocal ovarian transplants between young and old mothers indicate that the incidence of heart defects correlates with the age of the mother and not the oocyte, which implicates a maternal pathway as the basis of the risk. The quantitative risk varies between strain backgrounds, so maternal genetic polymorphisms determine the activity of a factor or factors in the pathway. Most strikingly, voluntary exercise by the mother mitigates the risk. Therefore, congenital heart disease can in principle be prevented by targeting a maternal pathway even if the embryo carries a causative mutation. Further mechanistic insight is necessary to develop an intervention that could be implemented on a broad scale, but the physiology of maternal-fetal interactions, aging, and exercise are notoriously complex and undefined. This suggests that an unbiased genetic approach would most efficiently lead to the relevant pathway. A genetic foundation would lay the groundwork for human studies and clinical trials.
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Affiliation(s)
- Patrick Y Jay
- Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA; Departments of Genetics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
| | - Ehiole Akhirome
- Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
| | - Rachel A Magnan
- Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
| | - M Rebecca Zhang
- Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
| | - Lillian Kang
- Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
| | - Yidan Qin
- Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
| | - Nelson Ugwu
- Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
| | - Suk Dev Regmi
- Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
| | - Julie M Nogee
- Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
| | - James M Cheverud
- Department of Biology, Loyola University Chicago, Chicago, IL, USA
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Burns T, Yang Y, Hiriart E, Wessels A. The Dorsal Mesenchymal Protrusion and the Pathogenesis of Atrioventricular Septal Defects. J Cardiovasc Dev Dis 2016; 3. [PMID: 28133602 PMCID: PMC5267359 DOI: 10.3390/jcdd3040029] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Congenital heart malformations are the most common type of defects found at birth. About 1% of infants are born with one or more heart defect on a yearly basis. Congenital Heart Disease (CHD) causes more deaths in the first year of life than any other congenital abnormality, and each year, nearly twice as many children die in the United States from CHD as from all forms of childhood cancers combined. Atrioventricular septal defects (AVSD) are congenital heart malformations affecting approximately 1 in 2000 live births. Babies born with an AVSD often require surgical intervention shortly after birth. However, even after successful surgery, these individuals typically have to deal with lifelong complications with the most common being a leaky mitral valve. In recent years the understanding of the molecular etiology and morphological mechanisms associated with the pathogenesis of AVSDs has significantly changed. Specifically, these studies have linked abnormal development of the Dorsal Mesenchymal Protrusion (DMP), a Second Heart Field-derived structure, to the development of this congenital defect. In this review we will be discuss some of the latest insights into the role of the DMP in the normal formation of the atrioventricular septal complex and in the pathogenesis of AVSDs.
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Affiliation(s)
- Tara Burns
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; (T.B.); (Y.Y.); (E.H.)
| | - Yanping Yang
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; (T.B.); (Y.Y.); (E.H.)
- Department of Histology and Embryology, Shanxi Medical University, No 56 Xin Jian Nan Road, Taiyuan 030001, Shanxi, China
| | - Emilye Hiriart
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; (T.B.); (Y.Y.); (E.H.)
| | - Andy Wessels
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; (T.B.); (Y.Y.); (E.H.)
- Correspondence: ; Tel.: +1-843-792-8183
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Xie X, Shi X, Xun X, Rao L. Associations of NKX2-5 Genetic Polymorphisms with the Risk of Congenital Heart Disease: A Meta-analysis. Pediatr Cardiol 2016; 37:953-61. [PMID: 27033241 DOI: 10.1007/s00246-016-1377-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 03/21/2016] [Indexed: 01/24/2023]
Abstract
The NKX2-5 gene is a vital regulator of cardiac formation and development. Recently, the roles of NKX2-5 63A>G polymorphism and 606G>C polymorphism in congenital heart disease (CHD) have been extensively studied, with conflicting results. The aim of the present study was to better elucidate the associations between NKX2-5 genetic polymorphisms and CHD risk through a meta-analysis. Eligible articles were searched in PubMed, MEDLINE, EMBASE, Google Scholar and CNKI up to December 2015. Odds ratios (ORs) and 95 % confidence intervals were used to detect any potential associations between NKX2-5 genetic polymorphisms and CHD risk. Heterogeneity between studies was assessed with Q test and I (2) statistic. Subgroup analysis and sensitivity analysis were performed to test the reliability and stability of the results, and funnel plots were applied to estimate publication bias. A total of 13 case-control studies including 2245 CHD patients and 1953 healthy controls were analyzed. The overall meta-analysis results showed that NKX2-5 63A>G polymorphism and 606G>C polymorphism were not significantly associated with CHD risk. Subgroup analysis was further performed for NKX2-5 63A>G polymorphism based on types of CHD and ethnicity of study population, and similar negative results were found in all subgroups. Our findings suggested that NKX2-5 63A>G polymorphism and 606G>C polymorphism may not be implicated in the pathogenesis of CHD.
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Affiliation(s)
- Xiaochuan Xie
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaohan Shi
- Division of Reproductive Medical Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoshuang Xun
- West China School of Public Health, Sichuan University, Chengdu, Sichuan, China
| | - Li Rao
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Zhang K, Song F, Zhang D, Liu Y, Zhang H, Wang Y, Dong R, Zhang Y, Liu Y, Gai Z. Chromosome r(3)(p25.3q29) in a Patient with Developmental Delay and Congenital Heart Defects: A Case Report and a Brief Literature Review. Cytogenet Genome Res 2016; 148:6-13. [PMID: 27077748 DOI: 10.1159/000445273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Indexed: 11/19/2022] Open
Abstract
Ring chromosome 3, r(3), is an extremely rare cytogenetic abnormality with clinical heterogeneity and only 12 cases reported in the literature. Here, we report a 1-year-old girl presenting distinctive facial features, developmental delay, and congenital heart defects with r(3) and a ∼10-Mb deletion of chromosome 3pterp25.3 (61,891-9,979,408) involving 42 known genes which was detected using G-banding karyotyping and CytoScan 750K-Array. The breakpoints in r(3) were mapped at 3p25.3 and 3q29. We also analyzed the available information on the clinical features of the reported cases with r(3) and 3p deletion syndrome in order to provide more valuable information of genotype-phenotype correlations. To our knowledge, this is the largest detected fragment described in r(3) cases and the second r(3) study using whole-genome microarray.
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Affiliation(s)
- Kaihui Zhang
- Pediatric Research Institute, Qilu Children's Hospital of Shandong University, Jinan, China
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Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier. Genetics 2016; 203:763-70. [PMID: 27029737 DOI: 10.1534/genetics.116.188045] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 03/19/2016] [Indexed: 01/14/2023] Open
Abstract
Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of >100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1 No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models.
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Chaix MA, Andelfinger G, Khairy P. Genetic testing in congenital heart disease: A clinical approach. World J Cardiol 2016; 8:180-191. [PMID: 26981213 PMCID: PMC4766268 DOI: 10.4330/wjc.v8.i2.180] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 10/16/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Congenital heart disease (CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient follow-up. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel.
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Atrioventricular septal defect: From embryonic development to long-term follow-up. Int J Cardiol 2016; 202:784-95. [DOI: 10.1016/j.ijcard.2015.09.081] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 07/28/2015] [Accepted: 09/23/2015] [Indexed: 11/18/2022]
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