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van den Dolder FW, Dinani R, Warnaar VAJ, Vučković S, Passadouro AS, Nassar AA, Ramsaroep AX, Burchell GB, Schoonmade LJ, van der Velden J, Goversen B. Experimental Models of Hypertrophic Cardiomyopathy: A Systematic Review. JACC Basic Transl Sci 2025; 10:511-546. [PMID: 40306862 DOI: 10.1016/j.jacbts.2024.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 05/02/2025]
Abstract
To advance research in hypertrophic cardiomyopathy (HCM), and guide researchers in choosing the optimal model to answer their research questions, we performed a systematic review of all models investigating HCM induced by gene variants ranging from animal models to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Our research question entailed: which experimental models of HCM have been created thus far, and which major hallmarks of HCM do they present? Out of the 603 included papers, the majority included animal models, though a clear transition to hiPSC-CM is visible since 2010. Our review showed that only 36 mouse models showed minimal 4 out of 6 HCM disease markers (cell/cardiac hypertrophy, disarray, fibrosis, diastolic dysfunction, and arrhythmias), while only 17 hiPSC-CM models showed 3 out of 4 HCM cell characteristics. Our review emphasizes the need to better report data on sample size, sex, age, and relevant disease-specific characteristics.
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Affiliation(s)
- Floor W van den Dolder
- Department of Physiology, Amsterdam University Medical Center (UMC), Location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - Rafeeh Dinani
- Department of Physiology, Amsterdam University Medical Center (UMC), Location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - Vincent A J Warnaar
- Department of Physiology, Amsterdam University Medical Center (UMC), Location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - Sofija Vučković
- Department of Physiology, Amsterdam University Medical Center (UMC), Location VUmc, Amsterdam, the Netherlands; Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Adriana S Passadouro
- Department of Physiology, Amsterdam University Medical Center (UMC), Location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands; Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, the Netherlands
| | - Ali A Nassar
- Department of Physiology, Amsterdam University Medical Center (UMC), Location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
| | - Azhaar X Ramsaroep
- Department of Physiology, Amsterdam University Medical Center (UMC), Location VUmc, Amsterdam, the Netherlands
| | - George B Burchell
- Medical Library, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Linda J Schoonmade
- Medical Library, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Jolanda van der Velden
- Department of Physiology, Amsterdam University Medical Center (UMC), Location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands.
| | - Birgit Goversen
- Department of Physiology, Amsterdam University Medical Center (UMC), Location VUmc, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, the Netherlands
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2
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Li G, Zhao C, Wu L, Yan Y. Rapid progression of right ventricular dysfunction: a case report. BMC Cardiovasc Disord 2025; 25:157. [PMID: 40055607 PMCID: PMC11887079 DOI: 10.1186/s12872-025-04601-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 02/24/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND Arrhythmogenic cardiomyopathy (ACM) is a genetic myocardial disease characterized by progressive myocyte loss and fibrofatty (fibrous and adipose) tissue replacement to predispose these patients to fatal ventricular arrhythmias and impairment of ventricular systolic function. The relationship of ACM and myocarditis has gained significant attention. CASE PRESENTATION This case presented a 28-year-old female who was admitted to the hospital with complaints of recurrent lower limb edema and palpitations for 6 months. Her electrocardiogram revealed a typical manifestation of an advanced form of biventricular arrhythmogenic cardiomyopathy (ACM). Despite systematic medical management, her right ventricle (RV) function deteriorated rapidly, necessitating heart transplantation. Postoperative histopathological examinations confirmed the RV involvement as reflected in the electrocardiogram. Especially, multiple foci of lymphocytic infiltration were observed throughout the heart, with the RV being the most severe. CONCLUSION When a rapid progression of ACM occurs, a concomitant myocarditis should be considered. ACM may be an inflammation-mediated transformation from myocardial tissue to fibrofatty tissue, and myocarditis may be a part of the natural history in some ACM cases.
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Affiliation(s)
- Guoliang Li
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Changying Zhao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, China
| | - Lingmin Wu
- Arrhythmia Center, Peking Union Medical College, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Fuwai Hospital, Beijing, China
| | - Yang Yan
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, China.
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3
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Bakhtiarizade MR, Heidari M, Ghanatghestani AHM. Comprehensive circular RNA profiling in various sheep tissues. Sci Rep 2024; 14:26238. [PMID: 39482374 PMCID: PMC11527890 DOI: 10.1038/s41598-024-76940-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 10/17/2024] [Indexed: 11/03/2024] Open
Abstract
Despite the scientific relevance of circular RNAs (circRNAs), the study of these RNAs in non-model organisms, especially in sheep, is still in its infancy. On the other hand, while some studies have focused on sheep circRNA identification in a limited number of tissues, there is a lack of comprehensive analysis that profile circRNA expression patterns across the tissues not yet investigated. In this study, 61 public RNA sequencing datasets from 12 different tissues were uniformly analyzed to identify circRNAs, profile their expression and investigate their various characteristics. We reported for the first time a circRNA expression landscape with functional annotation in sheep tissues not yet investigated including hippocampus, BonMarrowMacrophage, left-ventricle, thymus, ileum, reticulum and 23-day-embryo. A stringent computational pipeline was employed and 8919 exon-derived circRNAs with high confidence were identified, including 88 novel circRNAs. Tissue-specificity analysis revealed that 3059 circRNAs were tissue-specific, which were also more specific to the tissues than linear RNAs. The highest number of tissue-specific circRNAs was found in kidney, hippocampus and thymus, respectively. Co-expression analysis revealed that expression of circRNAs may not be affected by their host genes. While most of the host genes produced more than one isoform, only one isoform had dominant expression across the tissues. The host genes of the tissue-specific circRNAs were significantly enriched in biological/pathways terms linked to the important functions of their corresponding tissues, suggesting potential roles of circRNAs in modulating physiological activity of those tissues. Interestingly, functional terms related to the regulation and various signaling pathways were significantly enriched in all tissues, suggesting some common regulatory mechanisms of circRNAs to modulate the physiological functions of tissues. Finding of the present study provide a valuable resource for depicting the complexity of circRNAs expression across tissues of sheep, which can be useful for the field of sheep genomic and veterinary research.
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Affiliation(s)
| | - Maryam Heidari
- Department of Animal Sciences, College of Agriculture, Isfahan University of Technology, Isfahan, Iran
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Newman NA, Burke MA. Dilated Cardiomyopathy: A Genetic Journey from Past to Future. Int J Mol Sci 2024; 25:11460. [PMID: 39519012 PMCID: PMC11546582 DOI: 10.3390/ijms252111460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation. Cases without an identified secondary cause are classified as idiopathic dilated cardiomyopathy (IDC). Over the last 35 years, many cases of IDC have increasingly been recognized to be genetic in etiology with a core set of definitively causal genes in up to 40% of cases. While over 200 genes have been associated with DCM, the evidence supporting pathogenicity for most remains limited. Further, rapid advances in sequencing and bioinformatics have recently revealed a complex genetic spectrum ranging from monogenic to polygenic in DCM. These advances have also led to the discovery of causal and modifier genetic variants in secondary forms of DCM (e.g., alcohol-induced cardiomyopathy). Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies (e.g., device placement in LMNA cardiomyopathy). The future of genetics in DCM will likely involve polygenic risk scores, direct-to-consumer testing, and pharmacogenetics, requiring providers to have a thorough understanding of this rapidly developing field. Herein we outline three decades of genetics in DCM, summarize recent advances, and project possible future avenues for the field.
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Affiliation(s)
- Noah A. Newman
- Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Michael A. Burke
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA
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5
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Xu X, Wang X, Li Y, Chen R, Wen H, Wang Y, Ma G. Research progress of ankyrin repeat domain 1 protein: an updated review. Cell Mol Biol Lett 2024; 29:131. [PMID: 39420247 PMCID: PMC11488291 DOI: 10.1186/s11658-024-00647-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 09/27/2024] [Indexed: 10/19/2024] Open
Abstract
Ankyrin repeat domain 1 (Ankrd1) is an acute response protein that belongs to the muscle ankyrin repeat protein (MARP) family. Accumulating evidence has revealed that Ankrd1 plays a crucial role in a wide range of biological processes and diseases. This review consolidates current knowledge on Ankrd1's functions in myocardium and skeletal muscle development, neurogenesis, cancer, bone formation, angiogenesis, wound healing, fibrosis, apoptosis, inflammation, and infection. The comprehensive profile of Ankrd1 in cardiovascular diseases, myopathy, and its potential as a candidate prognostic and diagnostic biomarker are also discussed. In the future, more studies of Ankrd1 are warranted to clarify its role in diseases and assess its potential as a therapeutic target.
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Affiliation(s)
- Xusan Xu
- Maternal and Child Research Institute, Shunde Women and Children Hospital, Guangdong Medical University, Foshan, 528300, China
| | - Xiaoxia Wang
- Department of Neurology, Longjiang Hospital, Foshan, 528300, China
| | - Yu Li
- Department of Pediatrics, Shunde Women and Children Hospital, Guangdong Medical University, Foshan, 528300, China
| | - Riling Chen
- Department of Pediatrics, Shunde Women and Children Hospital, Guangdong Medical University, Foshan, 528300, China
| | - Houlang Wen
- Medical Genetics Laboratory, Shunde Women and Children Hospital, Guangdong Medical University, Foshan, 528300, China.
| | - Yajun Wang
- Respiratory Research Institute, Shunde Women and Children Hospital, Guangdong Medical University, Foshan, 528300, China.
| | - Guoda Ma
- Maternal and Child Research Institute, Shunde Women and Children Hospital, Guangdong Medical University, Foshan, 528300, China.
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6
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Micolonghi C, Perrone F, Fabiani M, Caroselli S, Savio C, Pizzuti A, Germani A, Visco V, Petrucci S, Rubattu S, Piane M. Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review. Int J Mol Sci 2024; 25:9787. [PMID: 39337275 PMCID: PMC11431948 DOI: 10.3390/ijms25189787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/04/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Hereditary cardiomyopathies (CMPs), including arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM), represent a group of heart disorders that significantly contribute to cardiovascular morbidity and mortality and are often driven by genetic factors. Recent advances in next-generation sequencing (NGS) technology have enabled the identification of rare variants in both well-established and minor genes associated with CMPs. Nowadays, a set of core genes is included in diagnostic panels for ACM, DCM, and HCM. On the other hand, despite their lesser-known status, variants in the minor genes may contribute to disease mechanisms and influence prognosis. This review evaluates the current evidence supporting the involvement of the minor genes in CMPs, considering their potential pathogenicity and clinical significance. A comprehensive analysis of databases, such as ClinGen, ClinVar, and GeneReviews, along with recent literature and diagnostic guidelines provides a thorough overview of the genetic landscape of minor genes in CMPs and offers guidance in clinical practice, evaluating each case individually based on the clinical referral, and insights for future research. Given the increasing knowledge on these less understood genetic factors, future studies are essential to clearly assess their roles, ultimately leading to improved diagnostic precision and therapeutic strategies in hereditary CMPs.
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Affiliation(s)
- Caterina Micolonghi
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy
| | - Federica Perrone
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy
- Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Marco Fabiani
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy
- ALTAMEDICA, Human Genetics, 00198 Rome, Italy
| | - Silvia Caroselli
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy
- Juno Genetics, Reproductive Genetics, 00188 Rome, Italy
| | | | - Antonio Pizzuti
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy
- Medical Genetics Unit, IRCCS Mendel Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Aldo Germani
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
| | - Vincenzo Visco
- S. Andrea University Hospital, 00189 Rome, Italy
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
| | - Simona Petrucci
- S. Andrea University Hospital, 00189 Rome, Italy
- Medical Genetics Unit, IRCCS Mendel Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
| | - Speranza Rubattu
- S. Andrea University Hospital, 00189 Rome, Italy
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
- IRCCS Neuromed, 86077 Pozzilli, Italy
| | - Maria Piane
- S. Andrea University Hospital, 00189 Rome, Italy
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy
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7
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Orgil BO, Purevjav E. Molecular Pathways and Animal Models of Cardiomyopathies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1441:991-1019. [PMID: 38884766 DOI: 10.1007/978-3-031-44087-8_64] [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
Cardiomyopathies are a heterogeneous group of disorders of the heart muscle that ultimately result in congestive heart failure. Rapid progress in genetics, molecular and cellular biology with breakthrough innovative genetic-engineering techniques, such as next-generation sequencing and multiomics platforms, stem cell reprogramming, as well as novel groundbreaking gene-editing systems over the past 25 years has greatly improved the understanding of pathogenic signaling pathways in inherited cardiomyopathies. This chapter will focus on intracellular and intercellular molecular signaling pathways that are activated by a genetic insult in cardiomyocytes to maintain tissue and organ level regulation and resultant cardiac remodeling in certain forms of cardiomyopathies. In addition, animal models of different clinical forms of human cardiomyopathies with their summaries of triggered key molecules and signaling pathways will be described.
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Affiliation(s)
- Buyan-Ochir Orgil
- Department of Pediatrics, The Heart Institute, Division of Cardiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Enkhsaikhan Purevjav
- Department of Pediatrics, The Heart Institute, Division of Cardiology, University of Tennessee Health Science Center, Memphis, TN, USA.
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8
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Zampieri M, Di Filippo C, Zocchi C, Fico V, Golinelli C, Spaziani G, Calabri G, Bennati E, Girolami F, Marchi A, Passantino S, Porcedda G, Capponi G, Gozzini A, Olivotto I, Ragni L, Favilli S. Focus on Paediatric Restrictive Cardiomyopathy: Frequently Asked Questions. Diagnostics (Basel) 2023; 13:3666. [PMID: 38132249 PMCID: PMC10742619 DOI: 10.3390/diagnostics13243666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/21/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023] Open
Abstract
Restrictive cardiomyopathy (RCM) is characterized by restrictive ventricular pathophysiology determined by increased myocardial stiffness. While suspicion of RCM is initially raised by clinical evaluation and supported by electrocardiographic and echocardiographic findings, invasive hemodynamic evaluation is often required for diagnosis and management of patients during follow-up. RCM is commonly associated with a poor prognosis and a high incidence of heart failure, and PH is reported in paediatric patients with RCM. Currently, only a few therapies are available for specific RCM aetiologies. Early referral to centres for advanced heart failure treatment is often necessary. The aim of this review is to address questions frequently asked when facing paediatric patients with RCM, including issues related to aetiologies, clinical presentation, diagnostic process and prognosis.
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Affiliation(s)
- Mattia Zampieri
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
- Cardiomyopathy Unit, Careggi University Hospital, 50134 Florence, Italy
| | - Chiara Di Filippo
- Local Health Unit, Outpatient Cardiology Clinic, 84131 Salerno, Italy
| | - Chiara Zocchi
- Cardiovascular Department, San Donato Hospital, 52100 Arezzo, Italy
| | - Vera Fico
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
- Cardiomyopathy Unit, Careggi University Hospital, 50134 Florence, Italy
| | - Cristina Golinelli
- Pediatric Cardiology and Adult Congenital Heart Disease Program, Department of Cardio—Thoracic and Vascular Medicine, IRCCS Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy
| | - Gaia Spaziani
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
| | - Giovanni Calabri
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
| | - Elena Bennati
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
| | - Francesca Girolami
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
| | - Alberto Marchi
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
- Cardiomyopathy Unit, Careggi University Hospital, 50134 Florence, Italy
| | - Silvia Passantino
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
| | - Giulio Porcedda
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
| | - Guglielmo Capponi
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
| | - Alessia Gozzini
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
| | - Iacopo Olivotto
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
- Cardiomyopathy Unit, Careggi University Hospital, 50134 Florence, Italy
| | - Luca Ragni
- Pediatric Cardiology and Adult Congenital Heart Disease Program, Department of Cardio—Thoracic and Vascular Medicine, IRCCS Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy
| | - Silvia Favilli
- Pediatric Cardiology, Meyer Children’s University Hospital IRCCS, 50134 Florence, Italy (S.F.)
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Noureddine M, Gehmlich K. Structural and signaling proteins in the Z-disk and their role in cardiomyopathies. Front Physiol 2023; 14:1143858. [PMID: 36935760 PMCID: PMC10017460 DOI: 10.3389/fphys.2023.1143858] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
The sarcomere is the smallest functional unit of muscle contraction. It is delineated by a protein-rich structure known as the Z-disk, alternating with M-bands. The Z-disk anchors the actin-rich thin filaments and plays a crucial role in maintaining the mechanical stability of the cardiac muscle. A multitude of proteins interact with each other at the Z-disk and they regulate the mechanical properties of the thin filaments. Over the past 2 decades, the role of the Z-disk in cardiac muscle contraction has been assessed widely, however, the impact of genetic variants in Z-disk proteins has still not been fully elucidated. This review discusses the various Z-disk proteins (alpha-actinin, filamin C, titin, muscle LIM protein, telethonin, myopalladin, nebulette, and nexilin) and Z-disk-associated proteins (desmin, and obscurin) and their role in cardiac structural stability and intracellular signaling. This review further explores how genetic variants of Z-disk proteins are linked to inherited cardiac conditions termed cardiomyopathies.
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Affiliation(s)
- Maya Noureddine
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Katja Gehmlich
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford, United Kingdom
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10
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Orgil BO, Xu F, Munkhsaikhan U, Alberson NR, Bajpai AK, Johnson JN, Sun Y, Towbin JA, Lu L, Purevjav E. Echocardiography phenotyping in murine genetic reference population of BXD strains reveals significant QTLs associated with cardiac function and morphology. Physiol Genomics 2023; 55:51-66. [PMID: 36534598 PMCID: PMC9902221 DOI: 10.1152/physiolgenomics.00120.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 12/14/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
The genetic reference population of recombinant inbred BXD mice has been derived from crosses between C57BL/6J and DBA/2J strains. The DBA/2J parent exhibits cardiomyopathy phenotypes, whereas C57BL/6J has normal heart. BXD mice are sequenced for studying genetic interactions in cardiomyopathies. The study aimed to assess cardiomyopathy traits in BXDs and investigate the quantitative genetic architecture of those traits. Echocardiography, blood pressure, and cardiomyocyte size parameters obtained from 44 strains of BXD family (n > 5/sex) at 4-5 mo of age were associated with heart transcriptomes and expression quantitative trait loci (eQTL) mapping was performed. More than twofold variance in ejection fraction (EF%), fractional shortening (FS%), left ventricular volumes (LVVols), internal dimensions (LVIDs), mass (LVM), and posterior wall (LVPW) thickness was found among BXDs. In male BXDs, eQTL mapping identified Ndrg4 on chromosome 8 QTL to be positively correlated with LVVol and LVID and negatively associated with cardiomyocyte diameter. In female BXDs, significant QTLs were found on chromosomes 7 and 3 to be associated with LVPW and EF% and FS%, respectively, and Josd2, Dap3, and Tpm3 were predicted as strong candidate genes. Our study found variable cardiovascular traits among BXD strains and identified multiple associated QTLs, suggesting an influence of genetic background on expression of echocardiographic and cardiomyocyte diameter traits. Increased LVVol and reduced EF% and FS% represented dilated cardiomyopathy, whereas increased LV mass and wall thickness indicated hypertrophic cardiomyopathy traits. The BXD family is ideal for identifying candidate genes, causal and modifier, that influence cardiovascular phenotypes.NEW & NOTEWORTHY This study aimed to establish a cardiac phenotype-genotype correlation in murine genetic reference population of BXD RI strains by phenotyping the echocardiography, blood pressure, and cardiomyocyte diameter traits and associating each collected phenotype with genetic background. Our study identified several QTLs and candidate genes that have significant association with cardiac hypertrophy, ventricular dilation, and function including systolic hyperfunction and dysfunction.
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Affiliation(s)
- Buyan-Ochir Orgil
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee
| | - Fuyi Xu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee
- School of Pharmacy, Binzhou Medical University, Yantai, China
| | - Undral Munkhsaikhan
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Neely R Alberson
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee
| | - Akhilesh Kumar Bajpai
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Jason N Johnson
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee
| | - Yao Sun
- Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Jeffrey A Towbin
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee
- Pediatric Cardiology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Lu Lu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Enkhsaikhan Purevjav
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee
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Sun B, Kekenes-Huskey PM. Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling. Q Rev Biophys 2023; 56:e2. [PMID: 36628457 PMCID: PMC11070111 DOI: 10.1017/s003358352300001x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The cardiac sarcomere is a cellular structure in the heart that enables muscle cells to contract. Dozens of proteins belong to the cardiac sarcomere, which work in tandem to generate force and adapt to demands on cardiac output. Intriguingly, the majority of these proteins have significant intrinsic disorder that contributes to their functions, yet the biophysics of these intrinsically disordered regions (IDRs) have been characterized in limited detail. In this review, we first enumerate these myofilament-associated proteins with intrinsic disorder (MAPIDs) and recent biophysical studies to characterize their IDRs. We secondly summarize the biophysics governing IDR properties and the state-of-the-art in computational tools toward MAPID identification and characterization of their conformation ensembles. We conclude with an overview of future computational approaches toward broadening the understanding of intrinsic disorder in the cardiac sarcomere.
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Affiliation(s)
- Bin Sun
- Research Center for Pharmacoinformatics (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China
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Genome Editing and Pathological Cardiac Hypertrophy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1396:87-101. [DOI: 10.1007/978-981-19-5642-3_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
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13
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Yang Z, Chen J, Li H, Lin Y. Genotype-Phenotype Associations with Restrictive Cardiomyopathy Induced by Pathogenic Genetic Mutations. Rev Cardiovasc Med 2022; 23:185. [PMID: 39077162 PMCID: PMC11273878 DOI: 10.31083/j.rcm2306185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/11/2022] [Accepted: 03/21/2022] [Indexed: 07/31/2024] Open
Abstract
Restrictive cardiomyopathy (RCM) is an uncommon cardiac muscle disease characterized by impaired ventricular filling and severe diastolic dysfunction with or without systolic dysfunction. The patients with RCM present poor prognosis and high prevalence of sudden cardiac death, especially in the young. The etiology of RCM may be idiopathic, familial or acquired predispositions from various systemic diseases. The genetic background of familial RCM is often caused by mutations in genes encoding proteins of sarcomeres and a significant minority by mutations in non-sarcomeric proteins and transthyretin proteins. It is important to identify the associations between genotype and phenotype to guide clinical diagnosis and treatment. Here, we have summarized the reported index cases with RCM involving genetic etiology to date and highlighted the most significant phenotype results.
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Affiliation(s)
- Zhe Yang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, 523710 Dongguan, Guangdong, China
- Department of Endocrinology and Metabolism, Zhuhai Hospital Affiliated to Jinan University; The First Hospital Affiliated to Medical College of Macao University of Science and Technology, 519000 Zhuhai, Guangdong, China
| | - Jia Chen
- The Second Department of Cardiology, The Second People's Hospital of Guangdong Province, 510310 Guangzhou, Guangdong, China
| | - Hong Li
- The First Dongguan Affiliated Hospital, Guangdong Medical University, 523710 Dongguan, Guangdong, China
| | - Yubi Lin
- The First Dongguan Affiliated Hospital, Guangdong Medical University, 523710 Dongguan, Guangdong, China
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14
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Zheng M, Huang H, Zhu X, Ho H, Li L, Ji X. Clinical genetic testing in four highly suspected pediatric restrictive cardiomyopathy cases. BMC Cardiovasc Disord 2022; 22:240. [PMID: 35614389 PMCID: PMC9131548 DOI: 10.1186/s12872-022-02675-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 05/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Restrictive cardiomyopathy (RCM) presents a high risk for sudden cardiac death in pediatric patients. Constrictive pericarditis (CP) exhibits a similar clinical presentation to RCM and requires differential diagnosis. While mutations of genes that encode sarcomeric and cytoskeletal proteins may lead to RCM, infection, rather than gene mutation, is the main cause of CP. Genetic testing may be helpful in the clinical diagnosis of RCM. METHODS In this case series study, we screened for TNNI3, TNNT2, and DES gene mutations that are known to be etiologically linked to RCM in four pediatric patients with suspected RCM. RESULTS We identified one novel heterozygous mutation, c.517C>T (substitution, position 517 C → T) (amino acid conversion, p.Leu173Phe), and two already known heterozygous mutations, c.508C>T (substitution, position 508, C → T) (amino acid conversion, p.Arg170Trp) and c.575G>A (substitution, position 575, G → A) (amino acid conversion, p.Arg192His), in the TNNI3 gene in three of the four patients. CONCLUSION Our findings support the notion that genetic testing may be helpful in the clinical diagnosis of RCM.
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Affiliation(s)
- Min Zheng
- Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Infection and Immunity, 136 Zhongshan 2nd Road, Yu Zhong District, Chongqing, 400014, China
| | - Hong Huang
- Pediatric Department, North-Kuanren General Hospital of Chongqing, Chongqing, 401121, China
| | - Xu Zhu
- Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Infection and Immunity, 136 Zhongshan 2nd Road, Yu Zhong District, Chongqing, 400014, China
| | - Harvey Ho
- Auckland Bioengineering Institute, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Liling Li
- Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Infection and Immunity, 136 Zhongshan 2nd Road, Yu Zhong District, Chongqing, 400014, China
| | - Xiaojuan Ji
- Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Infection and Immunity, 136 Zhongshan 2nd Road, Yu Zhong District, Chongqing, 400014, China.
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15
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Kucher AN, Sleptcov AA, Nazarenko MS. Genetic Landscape of Dilated Cardiomyopathy. RUSS J GENET+ 2022. [DOI: 10.1134/s1022795422030085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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16
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Genetic Insights into Primary Restrictive Cardiomyopathy. J Clin Med 2022; 11:jcm11082094. [PMID: 35456187 PMCID: PMC9027761 DOI: 10.3390/jcm11082094] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 12/04/2022] Open
Abstract
Restrictive cardiomyopathy is a rare cardiac disease causing severe diastolic dysfunction, ventricular stiffness and dilated atria. In consequence, it induces heart failure often with preserved ejection fraction and is associated with a high mortality. Since it is a poor clinical prognosis, patients with restrictive cardiomyopathy frequently require heart transplantation. Genetic as well as non-genetic factors contribute to restrictive cardiomyopathy and a significant portion of cases are of unknown etiology. However, the genetic forms of restrictive cardiomyopathy and the involved molecular pathomechanisms are only partially understood. In this review, we summarize the current knowledge about primary genetic restrictive cardiomyopathy and describe its genetic landscape, which might be of interest for geneticists as well as for cardiologists.
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17
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Chintanaphol M, Orgil BO, Alberson NR, Towbin JA, Purevjav E. Restrictive cardiomyopathy: from genetics and clinical overview to animal modeling. Rev Cardiovasc Med 2022; 23:108. [PMID: 35345275 DOI: 10.31083/j.rcm2303108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/08/2021] [Accepted: 10/25/2021] [Indexed: 11/06/2022] Open
Abstract
Restrictive cardiomyopathy (RCM), a potentially devastating heart muscle disorder, is characterized by diastolic dysfunction due to abnormal muscle relaxation and myocardial stiffness resulting in restrictive filling of the ventricles. Diastolic dysfunction is often accompanied by left atrial or bi-atrial enlargement and normal ventricular size and systolic function. RCM is the rarest form of cardiomyopathy, accounting for 2-5% of pediatric cardiomyopathy cases, however, survival rates have been reported to be 82%, 80%, and 68% at 1-, 2-, and 5-years after diagnosis, respectively. RCM can be idiopathic, familial, or secondary to a systemic disorder, such as amyloidosis, sarcoidosis, and hereditary hemochromatosis. Approximately 30% of cases are familial RCM, and the genes that have been linked to RCM are cTnT, cTnI, MyBP-C, MYH7, MYL2, MYL3, DES, MYPN, TTN, BAG3, DCBLD2, LNMA, and FLNC. Increased Ca2+ sensitivity, sarcomere disruption, and protein aggregates are some of the few mechanisms of pathogenesis that have been revealed by studies utilizing cell lines and animal models. Additional exploration into the pathogenesis of RCM is necessary to create novel therapeutic strategies to reverse restrictive cardiomyopathic phenotypes.
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Affiliation(s)
- Michelle Chintanaphol
- College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA
| | - Buyan-Ochir Orgil
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN 38103, USA
| | - Neely R Alberson
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN 38103, USA
| | - Jeffrey A Towbin
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN 38103, USA
- Pediatric Cardiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Enkhsaikhan Purevjav
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN 38103, USA
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18
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Bang ML, Bogomolovas J, Chen J. Understanding the molecular basis of cardiomyopathy. Am J Physiol Heart Circ Physiol 2022; 322:H181-H233. [PMID: 34797172 PMCID: PMC8759964 DOI: 10.1152/ajpheart.00562.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 02/03/2023]
Abstract
Inherited cardiomyopathies are a major cause of mortality and morbidity worldwide and can be caused by mutations in a wide range of proteins located in different cellular compartments. The present review is based on Dr. Ju Chen's 2021 Robert M. Berne Distinguished Lectureship of the American Physiological Society Cardiovascular Section, in which he provided an overview of the current knowledge on the cardiomyopathy-associated proteins that have been studied in his laboratory. The review provides a general summary of the proteins in different compartments of cardiomyocytes associated with cardiomyopathies, with specific focus on the proteins that have been studied in Dr. Chen's laboratory.
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Affiliation(s)
- Marie-Louise Bang
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan Unit, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
| | - Julius Bogomolovas
- Division of Cardiovascular Medicine, Department of Medicine Cardiology, University of California, San Diego, La Jolla, California
| | - Ju Chen
- Division of Cardiovascular Medicine, Department of Medicine Cardiology, University of California, San Diego, La Jolla, California
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19
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Filomena MC, Yamamoto DL, Carullo P, Medvedev R, Ghisleni A, Piroddi N, Scellini B, Crispino R, D'Autilia F, Zhang J, Felicetta A, Nemska S, Serio S, Tesi C, Catalucci D, Linke WA, Polishchuk R, Poggesi C, Gautel M, Bang ML. Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload. eLife 2021; 10:e58313. [PMID: 34558411 PMCID: PMC8547954 DOI: 10.7554/elife.58313] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 09/23/2021] [Indexed: 12/13/2022] Open
Abstract
Myopalladin (MYPN) is a striated muscle-specific immunoglobulin domain-containing protein located in the sarcomeric Z-line and I-band. MYPN gene mutations are causative for dilated (DCM), hypertrophic, and restrictive cardiomyopathy. In a yeast two-hybrid screening, MYPN was found to bind to titin in the Z-line, which was confirmed by microscale thermophoresis. Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths. MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein levels, and increased desmoplakin and SORBS2 protein levels. Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC, suggesting that altered Ca2+ handling may contribute to the development of DCM in MKO mice.
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Affiliation(s)
- Maria Carmela Filomena
- Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unitMilanItaly
- IRCCS Humanitas Research HospitalMilanItaly
| | - Daniel L Yamamoto
- Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unitMilanItaly
| | - Pierluigi Carullo
- Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unitMilanItaly
- IRCCS Humanitas Research HospitalMilanItaly
| | - Roman Medvedev
- IRCCS Humanitas Research HospitalMilanItaly
- Department of Cardiac Surgery, University of VeronaVeronaItaly
| | - Andrea Ghisleni
- Randall Centre for Cell and Molecular Biophysics, King's College London BHF Centre of Research ExcellenceLondonUnited Kingdom
| | - Nicoletta Piroddi
- Department of Experimental and Clinical Medicine, University of FlorenceFlorenceItaly
| | - Beatrice Scellini
- Department of Experimental and Clinical Medicine, University of FlorenceFlorenceItaly
| | - Roberta Crispino
- Telethon Institute of Genetics and Medicine (TIGEM)PozzuoliItaly
| | | | - Jianlin Zhang
- Department of Medicine, University of California, San DiegoLa JollaUnited States
| | - Arianna Felicetta
- IRCCS Humanitas Research HospitalMilanItaly
- Humanitas UniversityPieve EmanueleItaly
| | | | | | - Chiara Tesi
- Department of Experimental and Clinical Medicine, University of FlorenceFlorenceItaly
| | | | - Wolfgang A Linke
- Institute of Physiology II, University of MuensterMuensterGermany
| | - Roman Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM)PozzuoliItaly
| | - Corrado Poggesi
- Department of Experimental and Clinical Medicine, University of FlorenceFlorenceItaly
| | - Mathias Gautel
- Randall Centre for Cell and Molecular Biophysics, King's College London BHF Centre of Research ExcellenceLondonUnited Kingdom
| | - Marie-Louise Bang
- Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unitMilanItaly
- IRCCS Humanitas Research HospitalMilanItaly
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20
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Kim KH, Pereira NL. Genetics of Cardiomyopathy: Clinical and Mechanistic Implications for Heart Failure. Korean Circ J 2021; 51:797-836. [PMID: 34327881 PMCID: PMC8484993 DOI: 10.4070/kcj.2021.0154] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 06/14/2021] [Indexed: 11/11/2022] Open
Abstract
Genetic cardiomyopathies are an important cause of sudden cardiac death across all age groups. Genetic testing in heart failure clinics is useful for family screening and providing individual prognostic insight. Obtaining a family history of at least three generations, including the creation of a pedigree, is recommended for all patients with primary cardiomyopathy. Additionally, when appropriate, consultation with a genetic counsellor can aid in the success of a genetic evaluation. Clinical screening should be performed on all first-degree relatives of patients with genetic cardiomyopathy. Genetics has played an important role in the understanding of different cardiomyopathies, and the field of heart failure (HF) genetics is progressing rapidly. Much research has also focused on distinguishing markers of risk in patients with cardiomyopathy using genetic testing. While these efforts currently remain incomplete, new genomic technologies and analytical strategies provide promising opportunities to further explore the genetic architecture of cardiomyopathies, afford insight into the early manifestations of cardiomyopathy, and help define the molecular pathophysiological basis for cardiac remodeling. Cardiovascular physicians should be fully aware of the utility and potential pitfalls of incorporating genetic test results into pre-emptive treatment strategies for patients in the preliminary stages of HF. Future work will need to be directed towards elucidating the biological mechanisms of both rare and common gene variants and environmental determinants of plasticity in the genotype-phenotype relationship. This future research should aim to further our ability to identify, diagnose, and treat disorders that cause HF and sudden cardiac death in young patients, as well as prioritize improving our ability to stratify the risk for these patients prior to the onset of the more severe consequences of their disease.
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Affiliation(s)
- Kyung Hee Kim
- Division of Cardiology, Incheon Sejong General Hospital, Incheon, Korea.
| | - Naveen L Pereira
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.,Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
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21
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Giri P, Mukhopadhyay A, Gupta M, Mohapatra B. Dilated cardiomyopathy: a new insight into the rare but common cause of heart failure. Heart Fail Rev 2021; 27:431-454. [PMID: 34245424 DOI: 10.1007/s10741-021-10125-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/25/2021] [Indexed: 12/26/2022]
Abstract
Heart failure is a global health burden responsible for high morbidity and mortality with a prevalence of greater than 60 million individuals worldwide. One of the major causes of heart failure is dilated cardiomyopathy (DCM), characterized by associated systolic dysfunction. During the last few decades, there have been remarkable advances in our understanding about the genetics of dilated cardiomyopathy. The genetic causes were initially thought to be associated with mutations in genes encoding proteins that are localized to cytoskeleton and sarcomere only; however, with the advancement in mechanistic understanding, the roles of ion channels, Z-disc, mitochondria, nuclear proteins, cardiac transcription factors (e.g., NKX-2.5, TBX20, GATA4), and the factors involved in calcium homeostasis have also been identified and found to be implicated in both familial and sporadic DCM cases. During past few years, next-generation sequencing (NGS) has been established as a diagnostic tool for genetic analysis and it has added significantly to the existing candidate gene list for DCM. The animal models have also provided novel insights to develop a better treatment strategy based on phenotype-genotype correlation, epigenetic and phenomic profiling. Most of the DCM biomarkers that are used in routine genetic and clinical testing are structural proteins, but during the last few years, the role of mi-RNA has also emerged as a biomarker due to their accessibility through noninvasive methods. Our increasing genetic knowledge can improve the clinical management of DCM by bringing clinicians and geneticists on one platform, thereby influencing the individualized clinical decision making and leading to precision medicine.
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Affiliation(s)
- Prerna Giri
- Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Uttar Pradesh, Varanasi-5, India
| | - Amrita Mukhopadhyay
- Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Uttar Pradesh, Varanasi-5, India
| | - Mohini Gupta
- Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Uttar Pradesh, Varanasi-5, India
| | - Bhagyalaxmi Mohapatra
- Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Uttar Pradesh, Varanasi-5, India.
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22
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Histopathological changes of myocytes in restrictive cardiomyopathy. Med Mol Morphol 2021; 54:289-295. [PMID: 34057638 DOI: 10.1007/s00795-021-00293-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 05/27/2021] [Indexed: 10/21/2022]
Abstract
Restrictive cardiomyopathy (RCM) is a rare primary myocardial disease, and its pathological features are yet to be determined. Restrictive cardiomyopathy with MHY7 mutation was diagnosed in a 65-year-old Japanese woman. Electron microscopy of a myocardial biopsy revealed electron-dense materials resulting from focal myocyte degeneration and necrosis as well as tubular structures and pseudo-inclusion bodies in some nuclei. These features may be associated with the pathogenesis of RCM.
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23
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Hypertrophic Cardiomyopathy and Primary Restrictive Cardiomyopathy: Similarities, Differences and Phenocopies. J Clin Med 2021; 10:jcm10091954. [PMID: 34062949 PMCID: PMC8125617 DOI: 10.3390/jcm10091954] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/26/2021] [Accepted: 04/28/2021] [Indexed: 12/14/2022] Open
Abstract
Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These “sarcomeric cardiomyopathies” also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for cascade family screening and therapy.
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The Role of Z-disc Proteins in Myopathy and Cardiomyopathy. Int J Mol Sci 2021; 22:ijms22063058. [PMID: 33802723 PMCID: PMC8002584 DOI: 10.3390/ijms22063058] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/07/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022] Open
Abstract
The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts.
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25
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Genetic Restrictive Cardiomyopathy: Causes and Consequences-An Integrative Approach. Int J Mol Sci 2021; 22:ijms22020558. [PMID: 33429969 PMCID: PMC7827163 DOI: 10.3390/ijms22020558] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 12/12/2022] Open
Abstract
The sarcomere as the smallest contractile unit is prone to alterations in its functional, structural and associated proteins. Sarcomeric dysfunction leads to heart failure or cardiomyopathies like hypertrophic (HCM) or restrictive cardiomyopathy (RCM) etc. Genetic based RCM, a very rare but severe disease with a high mortality rate, might be induced by mutations in genes of non-sarcomeric, sarcomeric and sarcomere associated proteins. In this review, we discuss the functional effects in correlation to the phenotype and present an integrated model for the development of genetic RCM.
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26
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Polavarapu K, Bardhan M, Anjanappa RM, Vengalil S, Preethish-Kumar V, Shingavi L, Chawla T, Nashi S, Mohan D, Arunachal G, Geetha TS, Ramprasad V, Nalini A. Nemaline Rod/Cap Myopathy Due to Novel Homozygous MYPN Mutations: The First Report from South Asia and Comprehensive Literature Review. J Clin Neurol 2021; 17:409-418. [PMID: 34184449 PMCID: PMC8242322 DOI: 10.3988/jcn.2021.17.3.409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 02/16/2021] [Accepted: 02/16/2021] [Indexed: 11/17/2022] Open
Abstract
Background and Purpose Pathogenic variants in the myopalladin gene (MYPN) are known to cause mildly progressive nemaline/cap myopathy. Only nine cases have been reported in the English literature. Methods A detailed evaluation was conducted of the clinical, muscle magnetic resonance imaging (MRI), and genetic findings of two unrelated adults with MYPN-related cap myopathy. Genetic analysis was performed using whole-exome sequencing. MRI was performed on a 1.5-T device in patient 1. Results Two unrelated adults born to consanguineous parents, a 28-year-old male and a 23-year-old female, were diagnosed with pathogenic variants in MYPN that cause cap myopathy. Both patients presented with early-onset, insidiously progressive, and minimally disabling proximodistal weakness with mild ptosis, facial weakness, and bulbar symptoms. Patient 1 had a prominent foot drop from the onset. Both patients were followed up at age 30 years, at which point serum creatine kinase concentrations were minimally elevated. There were no cardiac symptoms; electrocardiograms and two-dimensional echocardiograms were normal in both patients. Muscle MRI revealed preferential involvement of the glutei, posterior thigh muscles, and anterior leg muscles. Whole-exome sequencing revealed significant homozygous splice-site variants in both of the probands, affecting intron 10 of MYPN: c.1973+1G>C (patient 1) and c.1974-2A>C (patient 2). Conclusions This study elaborates on two patients with homozygous MYPN pathogenic variants, presenting as slowly progressive congenital myopathy. These patients are only the tenth and eleventh cases reported in the English literature, and the first from South Asia. The clinical phenotype reiterates the mild form of nemaline rod/cap myopathy. A comprehensive literature review is presented.
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Affiliation(s)
- Kiran Polavarapu
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India.,Children's Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, The Ottawa Hospital; Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada
| | - Mainak Bardhan
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Ram Murthy Anjanappa
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Seena Vengalil
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | | | - Leena Shingavi
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Tanushree Chawla
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Saraswati Nashi
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Dhaarini Mohan
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Gautham Arunachal
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | | | | | - Atchayaram Nalini
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India.
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Li L, Li Y, Timothy Sembiring Meliala I, Kasim V, Wu S. Biological roles of Yin Yang 2: Its implications in physiological and pathological events. J Cell Mol Med 2020; 24:12886-12899. [PMID: 32969187 PMCID: PMC7754051 DOI: 10.1111/jcmm.15919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/07/2020] [Accepted: 09/08/2020] [Indexed: 12/15/2022] Open
Abstract
Yin yang 2 (YY2) is a multifunctional zinc finger protein that belongs to the yin yang (YY) family. YY2 has dual function in regulating gene expression, as it could act either as a transcriptional activator or as a repressor of its target genes. YY2 could regulate genes that have been previously identified as targets of yin yang 1 (YY1), another member of the YY family, by binding to their common binding sequences. However, recent studies revealed that YY2 also has its own specific binding sequences, leading to its particular biological functions distinct from those of YY1. Furthermore, they have different levels or even opposite regulatory effects on common target genes, suggesting the importance of balanced YY1 and YY2 regulations in maintaining proper cellular homeostasis and biological functions. Recent studies revealed that YY2 plays crucial roles in maintaining stemness and regulating differentiation potential of embryonic stem cells, as well as in the development of the brain, nervous and cardiovascular systems. YY2 expression is also closely related to diseases, as it could act as a tumour suppressor gene that regulates tumour cell proliferation and metastasis. Moreover, YY2 is also involved in immune regulation and immune surveillance. Herein, we summarize recent perspectives regarding the regulatory functions of YY2, as well as its biological functions and relation with diseases.
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Affiliation(s)
- Lang Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China
| | - Yanjun Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China
| | - Ian Timothy Sembiring Meliala
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China
| | - Vivi Kasim
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China.,State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China
| | - Shourong Wu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China.,State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China
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Gozalo AS, Zerfas PM, Elkins WR, Gieseck RL. Retrospective Study of Intercalated Disk Defects Associated with Dilated Cardiomyopathy, Atrial Thrombosis, and Heart Failure in BALB/c Mice Deficient in IL4 Receptor α. Comp Med 2020; 70:266-276. [PMID: 32384942 PMCID: PMC7287387 DOI: 10.30802/aalas-cm-19-000059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/01/2019] [Accepted: 10/22/2019] [Indexed: 12/21/2022]
Abstract
An increased incidence of dilated cardiomyopathy and atrial thrombosis was noted in a breeding colony of BALB/c mice deficient in IL4 receptor α. The condition affected mice of both sexes and of various ages, and extensive testing (microbiology, serology, histopathology) failed to ascertain the cause. Transmission electron microscopy of heart samples showed structural defects in the myocardial intercalated disks, characterized by unorganized and heavily convoluted arrangement with lower density and less prominent desmosomes and adherens junctions, widening of the intercellular space, myofibrillar lysis adjacent to intercalated disks, occasional sarcomere lysis with marked myofiber degeneration, vacuolation, accumulation of cell debris, and myelin figures. The intercalated disk contains cell adhesion molecules that form cell junctions, allowing contraction coupling of cardiomyocytes and the electrical and mechanical connection between cardiac fibers. Thus, defects at this level result in poor myocardial contraction, intracardiac blood stagnation, and consequently cardiac dilation with clinical signs of heart failure. The background strain or, potentially, the Cre-loxP-mediated recombination system used to create these mice may have contributed to the elevated incidence of cardiomyopathy and atrial thrombosis in this colony. Due to the backcrossing breeding scheme used, we cannot discount the emergence and colonywide dissemination of a spontaneous mutation that affects the intercalated disk. This report underscores the importance of carefully monitoring genetically modified mice colonies for unexpected phenotypes that may result from spontaneous or unintended mutations or enhanced strain background pathology.
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Affiliation(s)
- Alfonso S Gozalo
- Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;,
| | - Patricia M Zerfas
- Pathology Service, Office of Research Services, National Institutes of Health, Bethesda, Maryland
| | - William R Elkins
- Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Richard L Gieseck
- Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
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Filomena MC, Yamamoto DL, Caremani M, Kadarla VK, Mastrototaro G, Serio S, Vydyanath A, Mutarelli M, Garofalo A, Pertici I, Knöll R, Nigro V, Luther PK, Lieber RL, Beck MR, Linari M, Bang M. Myopalladin promotes muscle growth through modulation of the serum response factor pathway. J Cachexia Sarcopenia Muscle 2020; 11:169-194. [PMID: 31647200 PMCID: PMC7015241 DOI: 10.1002/jcsm.12486] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 07/01/2019] [Accepted: 07/22/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Myopalladin (MYPN) is a striated muscle-specific, immunoglobulin-containing protein located in the Z-line and I-band of the sarcomere as well as the nucleus. Heterozygous MYPN gene mutations are associated with hypertrophic, dilated, and restrictive cardiomyopathy, and homozygous loss-of-function truncating mutations have recently been identified in patients with cap myopathy, nemaline myopathy, and congenital myopathy with hanging big toe. METHODS Constitutive MYPN knockout (MKO) mice were generated, and the role of MYPN in skeletal muscle was studied through molecular, cellular, biochemical, structural, biomechanical, and physiological studies in vivo and in vitro. RESULTS MKO mice were 13% smaller compared with wild-type controls and exhibited a 48% reduction in myofibre cross-sectional area (CSA) and significantly increased fibre number. Similarly, reduced myotube width was observed in MKO primary myoblast cultures. Biomechanical studies showed reduced isometric force and power output in MKO mice as a result of the reduced CSA, whereas the force developed by each myosin molecular motor was unaffected. While the performance by treadmill running was similar in MKO and wild-type mice, MKO mice showed progressively decreased exercise capability, Z-line damage, and signs of muscle regeneration following consecutive days of downhill running. Additionally, MKO muscle exhibited progressive Z-line widening starting from 8 months of age. RNA-sequencing analysis revealed down-regulation of serum response factor (SRF)-target genes in muscles from postnatal MKO mice, important for muscle growth and differentiation. The SRF pathway is regulated by actin dynamics as binding of globular actin to the SRF-cofactor myocardin-related transcription factor A (MRTF-A) prevents its translocation to the nucleus where it binds and activates SRF. MYPN was found to bind and bundle filamentous actin as well as interact with MRTF-A. In particular, while MYPN reduced actin polymerization, it strongly inhibited actin depolymerization and consequently increased MRTF-A-mediated activation of SRF signalling in myogenic cells. Reduced myotube width in MKO primary myoblast cultures was rescued by transduction with constitutive active SRF, demonstrating that MYPN promotes skeletal muscle growth through activation of the SRF pathway. CONCLUSIONS Myopalladin plays a critical role in the control of skeletal muscle growth through its effect on actin dynamics and consequently the SRF pathway. In addition, MYPN is important for the maintenance of Z-line integrity during exercise and aging. These results suggest that muscle weakness in patients with biallelic MYPN mutations may be associated with reduced myofibre CSA and SRF signalling and that the disease phenotype may be aggravated by exercise.
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Affiliation(s)
- Maria Carmela Filomena
- Institute of Genetic and Biomedical Research (IRGB), Milan UnitNational Research CouncilMilanItaly
- Humanitas Clinical and Research CenterRozzanoMilanItaly
| | - Daniel L. Yamamoto
- Institute of Genetic and Biomedical Research (IRGB), Milan UnitNational Research CouncilMilanItaly
| | - Marco Caremani
- Department of BiologyUniversity of FlorenceSesto FiorentinoFlorenceItaly
| | | | | | - Simone Serio
- Humanitas Clinical and Research CenterRozzanoMilanItaly
| | | | | | - Arcamaria Garofalo
- Telethon Institute of Genetics and Medicine (TIGEM)PozzuoliItaly
- Department of Precision MedicineUniversity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Irene Pertici
- Department of BiologyUniversity of FlorenceSesto FiorentinoFlorenceItaly
| | - Ralph Knöll
- Integrated Cardio Metabolic Centre (ICMC), Myocardial GeneticsKarolinska Institutet, University Hospital, Heart and Vascular ThemeSweden
- Research and Early Development, Cardiovascular, Renal and Metabolic Diseases (CVRM), Biopharmaceuticals R&DAstraZenecaMölndalSweden
| | - Vincenzo Nigro
- Telethon Institute of Genetics and Medicine (TIGEM)PozzuoliItaly
- Department of Precision MedicineUniversity of Campania “Luigi Vanvitelli”NaplesItaly
| | | | - Richard L. Lieber
- Shirley Ryan AbilityLab and Hines V.A. Medical Center ChicagoChicagoILUSA
- Department of Physical Medicine and RehabilitationNorthwestern UniversityChicagoILUSA
- Department of Orthopaedic SurgeryUniversity of California San DiegoLa JollaCAUSA
| | - Moriah R. Beck
- Department of ChemistryWichita State UniversityWichitaKSUSA
| | - Marco Linari
- Department of BiologyUniversity of FlorenceSesto FiorentinoFlorenceItaly
| | - Marie‐Louise Bang
- Institute of Genetic and Biomedical Research (IRGB), Milan UnitNational Research CouncilMilanItaly
- Humanitas Clinical and Research CenterRozzanoMilanItaly
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Mastroianno S, Palumbo P, Castellana S, Leone MP, Massaro R, Potenza DR, Mazza T, Russo A, Castori M, Carella M, Di Stolfo G. Double missense mutations in cardiac myosin-binding protein C and myopalladin genes: A case report with diffuse coronary disease, complete atrioventricular block, and progression to dilated cardiomyopathy. Ann Noninvasive Electrocardiol 2019; 25:e12687. [PMID: 31524317 DOI: 10.1111/anec.12687] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 08/12/2019] [Indexed: 12/25/2022] Open
Abstract
Cardiomyopathies caused by double gene mutations are rare but conferred a remarkably increased risk of end-stage progression, arrhythmias, and poor outcome. Compound genetic mutations leading to complex phenotype in the setting of cardiomyopathies represent an important challenge in clinical practice, and genetic tests allow risk stratification and personalized clinical management of patients. We report a case of a 50-year-old woman with congestive heart failure characterized by dilated cardiomyopathy, diffuse coronary disease, complete atrioventricular block, and missense mutations in cardiac myosin-binding protein C (MYBPC3) and myopalladin (MYPN). We discuss the plausible role of genetic profile in phenotype determination.
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Affiliation(s)
- Sandra Mastroianno
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Pietro Palumbo
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Stefano Castellana
- Bioinformatic Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo-Istituto Mendel, Roma, Italy
| | - Maria Pia Leone
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Raimondo Massaro
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Domenico Rosario Potenza
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Tommaso Mazza
- Bioinformatic Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo-Istituto Mendel, Roma, Italy
| | - Aldo Russo
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Marco Castori
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Massimo Carella
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Giuseppe Di Stolfo
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
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Brodehl A, Ebbinghaus H, Deutsch MA, Gummert J, Gärtner A, Ratnavadivel S, Milting H. Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies. Int J Mol Sci 2019; 20:ijms20184381. [PMID: 31489928 PMCID: PMC6770343 DOI: 10.3390/ijms20184381] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/29/2019] [Accepted: 09/03/2019] [Indexed: 12/17/2022] Open
Abstract
In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original discovery that pluripotency can be artificially induced by the expression of different transcription factors, various patient-specific-induced pluripotent stem cell lines have been generated to model non-ischemic, genetic cardiomyopathies in vitro. In this review, we describe the genetic landscape of non-ischemic, genetic cardiomyopathies and give an overview about different human iPSC lines, which have been developed for the disease modeling of inherited cardiomyopathies. We summarize different methods and protocols for the general differentiation of human iPSCs into cardiomyocytes. In addition, we describe methods and technologies to investigate functionally human iPSC-derived cardiomyocytes. Furthermore, we summarize novel genome editing approaches for the genetic manipulation of human iPSCs. This review provides an overview about the genetic landscape of inherited cardiomyopathies with a focus on iPSC technology, which might be of interest for clinicians and basic scientists interested in genetic cardiomyopathies.
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Affiliation(s)
- Andreas Brodehl
- Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
| | - Hans Ebbinghaus
- Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
| | - Marcus-André Deutsch
- Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, University Hospital Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
| | - Jan Gummert
- Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
- Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, University Hospital Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
| | - Anna Gärtner
- Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
| | - Sandra Ratnavadivel
- Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
| | - Hendrik Milting
- Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
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Merlini L, Sabatelli P, Antoniel M, Carinci V, Niro F, Monetti G, Torella A, Giugliano T, Faldini C, Nigro V. Congenital myopathy with hanging big toe due to homozygous myopalladin (MYPN) mutation. Skelet Muscle 2019; 9:14. [PMID: 31133047 PMCID: PMC6535860 DOI: 10.1186/s13395-019-0199-9] [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: 10/31/2018] [Accepted: 04/25/2019] [Indexed: 12/11/2022] Open
Abstract
Background Myopalladin (MYPN) is a component of the sarcomere that tethers nebulin in skeletal muscle and nebulette in cardiac muscle to alpha-actinin at the Z lines. Autosomal dominant MYPN mutations cause hypertrophic, dilated, or restrictive cardiomyopathy. Autosomal recessive MYPN mutations have been reported in only six families showing a mildly progressive nemaline or cap myopathy with cardiomyopathy in some patients. Case presentation A consanguineous family with congenital to adult-onset muscle weakness and hanging big toe was reported. Muscle biopsy showed minimal changes with internal nuclei, type 1 fiber predominance, and ultrastructural defects of Z line. Muscle CT imaging showed marked hypodensity of the sartorius bilaterally and MRI scattered abnormal high-intensity areas in the internal tongue muscle and in the posterior cervical muscles. Cardiac involvement was demonstrated by magnetic resonance imaging and late gadolinium enhancement. Whole exome sequencing analysis identified a homozygous loss of function single nucleotide deletion in the exon 11 of the MYPN gene in two siblings. Full-length MYPN protein was undetectable on immunoblotting, and on immunofluorescence, its localization at the Z line was missed. Conclusions This report extends the phenotypic spectrum of recessive MYPN-related myopathies showing: (1) the two patients had hanging big toe and the oldest one developed spine and hand contractures, none of these signs observed in the previously reported patients, (2) specific ultrastructural changes consisting in Z line fragmentation, but (3) no nemaline or caps on muscle pathology.
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Affiliation(s)
- Luciano Merlini
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Patrizia Sabatelli
- IRCCS-Istituto Ortopedico Rizzoli, Bologna, Italy.,Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy
| | - Manuela Antoniel
- Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy
| | | | - Fabio Niro
- Division of Cardiology, Hospital St. Orsola, Bologna, Italy
| | | | - Annalaura Torella
- Dipartimento di Medicina di Precisione, Università della Campania "Luigi Vanvitelli", Naples, Italy.,Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Teresa Giugliano
- Dipartimento di Medicina di Precisione, Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Cesare Faldini
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Clinic of Orthopaedic and Traumatology, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Vincenzo Nigro
- Dipartimento di Medicina di Precisione, Università della Campania "Luigi Vanvitelli", Naples, Italy. .,Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
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Herriges JC, Dugan SL, Lamb AN. Clinical and molecular cytogenetic characterization of a novel 10q interstitial deletion: a case report and review of the literature. Mol Cytogenet 2019; 12:20. [PMID: 31131026 PMCID: PMC6525357 DOI: 10.1186/s13039-019-0430-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 04/16/2019] [Indexed: 12/17/2022] Open
Abstract
Background There are only ten reported cases of interstitial deletions involving cytogenetic bands 10q21.3q22.2 in the literature. Of the ten patients with overlapping 10q21.3q22.2 interstitial deletions, only nine have been characterized by chromosomal microarray analysis. Here, we report a two-and-a-half-year-old patient with a de novo 10.2-Mb deletion that extends from 10q21.3 to 10q22.3 and contains 92 protein coding genes. Case presentation The patient is the product of a 37-week dizygotic twin pregnancy and presented with global developmental delay, hypotonia, feeding difficulties, short stature, poor weight gain, scaphocephaly, retrognathia, hypoplasia of the optic nerves/chiasms, a distinctive facial gestalt, as well as additional minor dysmorphic features. The deletion identified in our patient is the second largest reported interstitial deletion involving the 10q21.3q22.2 region. Our patient presents with the generalized features observed in 10q21.3q22.2 deletion patients and also presents with several novel findings including scaphocephaly, hypoplasia of the optic nerves and chiasms, and a very distinctive facial gestalt. Conclusions Based on a literature review, we identify a commonly deleted region and suggest that KAT6B is a critical gene within the 10q21.3q22.2 region. However, a review of the reported overlapping deletions also suggests that there are additional critical genes contributing to the clinical presentation of these patients. Electronic supplementary material The online version of this article (10.1186/s13039-019-0430-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- John C Herriges
- 1Department of Pathology, University of Utah, Salt Lake City, UT USA.,2ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108 USA
| | - Sarah L Dugan
- 3Department of Pediatric Medical Genetics, University of Utah, Salt Lake City, USA
| | - Allen N Lamb
- 1Department of Pathology, University of Utah, Salt Lake City, UT USA.,2ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108 USA
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Abstract
The congenital myopathies form a large clinically and genetically heterogeneous group of disorders. Currently mutations in at least 27 different genes have been reported to cause a congenital myopathy, but the number is expected to increase due to the accelerated use of next-generation sequencing methods. There is substantial overlap between the causative genes and the clinical and histopathologic features of the congenital myopathies. The mode of inheritance can be autosomal recessive, autosomal dominant or X-linked. Both dominant and recessive mutations in the same gene can cause a similar disease phenotype, and the same clinical phenotype can also be caused by mutations in different genes. Clear genotype-phenotype correlations are few and far between.
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Affiliation(s)
- Katarina Pelin
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Folkhälsan Research Center, and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
| | - Carina Wallgren-Pettersson
- The Folkhälsan Institute of Genetics, Folkhälsan Research Center, and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
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35
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Refaat MM, Hassanieh S, Ballout JA, Zakka P, Hotait M, Khalil A, Bitar F, Arabi M, Arnaout S, Skouri H, Abchee A, Abi-Saleh B, Khoury M, Massouras A, Nemer G. Non-familial cardiomyopathies in Lebanon: exome sequencing results for five idiopathic cases. BMC Med Genomics 2019; 12:33. [PMID: 30764827 PMCID: PMC6375196 DOI: 10.1186/s12920-019-0478-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Accepted: 01/29/2019] [Indexed: 12/21/2022] Open
Abstract
Background Cardiomyopathies affect more than 0.5% of the general population. They are associated with high risk of sudden cardiac death, which can result from either heart failure or electrical abnormalities. Although different mechanisms underlie the various types of cardiomyopathies, a principal pathology is common to all and is usually at the level of the cardiac muscle. With a relatively high incidence rate in most countries, and a subsequent major health burden on both the families and governments, cardiomyopathies are gaining more attention by researchers and pharmaceutical companies as well as health government bodies. In Lebanon, there is no official data about the spectrum of the diseases in terms of their respective prevalence, clinical, or genetic profiles. Methods We used exome sequencing to unravel the genetic basis of idiopathic cases of cardiomyopathies in Lebanon, a relatively small country with high rates of consanguineous marriages. Results Five cases were diagnosed with different forms of cardiomyopathies, and exome sequencing revealed the presence of already documented or novel mutations in known genes in three cases: LMNA for an Emery Dreifuss Muscular Dystrophy case, PKP2 for an arrhythmogenic right ventricle dysplasia case, and MYPN for a dilated cardiomyopathy case. Interestingly two brothers with hypertrophic cardiomyopathy have a novel missense variation in NPR1, the gene encoding the natriuretic peptides receptor type I, not reported previously to be causing cardiomyopathies. Conclusion Our results unravel novel mutations in known genes implicated in cardiomyopathies in Lebanon. Changes in clinical management however, require genetic profiling of a larger cohort of patients. Electronic supplementary material The online version of this article (10.1186/s12920-019-0478-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Marwan M Refaat
- Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon. .,Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon.
| | - Sylvana Hassanieh
- Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | - Jad A Ballout
- Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | - Patrick Zakka
- Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | - Mostafa Hotait
- Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | - Athar Khalil
- Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | - Fadi Bitar
- Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon
| | - Mariam Arabi
- Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon
| | - Samir Arnaout
- Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | - Hadi Skouri
- Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | - Antoine Abchee
- Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | - Bernard Abi-Saleh
- Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | - Maurice Khoury
- Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
| | | | - Georges Nemer
- Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine and Medical Center (AUBMC), Phase I, 8th floor, Room C-823, PO Box 11-0236, Riad El-Solh, Beirut, 1107 2020, Lebanon
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36
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Translating emerging molecular genetic insights into clinical practice in inherited cardiomyopathies. J Mol Med (Berl) 2018; 96:993-1024. [PMID: 30128729 DOI: 10.1007/s00109-018-1685-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 07/22/2018] [Accepted: 08/08/2018] [Indexed: 12/19/2022]
Abstract
Cardiomyopathies are primarily genetic disorders of the myocardium associated with higher risk of life-threatening cardiac arrhythmias, heart failure, and sudden cardiac death. The evolving knowledge in genomic medicine during the last decade has reshaped our understanding of cardiomyopathies as diseases of multifactorial nature and complex pathophysiology. Genetic testing in cardiomyopathies has subsequently grown from primarily a research tool into an essential clinical evaluation piece with important clinical implications for patients and their families. The purpose of this review is to provide with a contemporary insight into the implications of genetic testing in diagnosis, therapy, and prognosis of patients with inherited cardiomyopathies. Here, we summarize the contemporary knowledge on genotype-phenotype correlations in inherited cardiomyopathies and highlight the recent significant achievements in the field of translational cardiovascular genetics.
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Walsh R, Buchan R, Wilk A, John S, Felkin LE, Thomson KL, Chiaw TH, Loong CCW, Pua CJ, Raphael C, Prasad S, Barton PJ, Funke B, Watkins H, Ware JS, Cook SA. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. Eur Heart J 2018; 38:3461-3468. [PMID: 28082330 PMCID: PMC5837460 DOI: 10.1093/eurheartj/ehw603] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 11/24/2016] [Indexed: 12/31/2022] Open
Abstract
Aim Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM. Methods and results We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence. Conclusion We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients.
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Affiliation(s)
- Roddy Walsh
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.,Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK
| | - Rachel Buchan
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.,Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK
| | - Alicja Wilk
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.,Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK
| | - Shibu John
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.,Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK
| | - Leanne E Felkin
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.,Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK
| | - Kate L Thomson
- Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.,Radcliffe Department of Medicine, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
| | - Tang Hak Chiaw
- National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore
| | - Calvin Chin Woon Loong
- National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore
| | - Chee Jian Pua
- National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore
| | - Claire Raphael
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
| | - Sanjay Prasad
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
| | - Paul J Barton
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK.,Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK
| | - Birgit Funke
- Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, 65 Lansdowne Street, Cambridge, MA 02139, USA.,Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
| | - Hugh Watkins
- Radcliffe Department of Medicine, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.,The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK
| | - James S Ware
- Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.,Cardiovascular Magnetic Resonance Imaging and Genetics, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
| | - Stuart A Cook
- Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK.,National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore.,Cardiovascular Magnetic Resonance Imaging and Genetics, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.,Division of Cardiovascular & Metabolic Disorders, Duke-National University of Singapore, 8 College Road, 169857 Singapore, Singapore
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Acute multi-visceral thrombosis and ischemia in a 3-year-old child. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2018. [DOI: 10.1016/j.epsc.2018.04.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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39
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Genetic background of Japanese patients with pediatric hypertrophic and restrictive cardiomyopathy. J Hum Genet 2018; 63:989-996. [PMID: 29907873 DOI: 10.1038/s10038-018-0479-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 05/28/2018] [Accepted: 05/29/2018] [Indexed: 01/28/2023]
Abstract
Hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) present a high risk for sudden cardiac death in pediatric patients. The aim of this study was to identify disease-associated genetic variants in Japanese patients with pediatric HCM and RCM. We analyzed 67 cardiomyopathy-associated genes in 46 HCM and 7 RCM patients diagnosed before 16 years of age using a next-generation sequencing system. We found that 78% of HCM and 71% of RCM patients carried disease-associated genetic variants. Disease-associated genetic variants were identified in 80% of HCM patients with a family history and in 77% of HCM patients with no apparent family history (NFH). MYH7 and/or MYBPC3 variants comprised 76% of HCM-associated variants, whereas troponin complex-encoding genes comprised 75% of the RCM-associated variants. In addition, 91% of HCM patients with implantable cardioverter-defibrillators and infant cases had NFH, and the 88% of HCM patients carrying disease-associated genetic variants were males who carried MYH7 or MYBPC3 variants. Moreover, two disease-associated LAMP2, one DES and one FHOD3 variants, were identified in HCM patients. In this study, pediatric HCM and RCM patients were found to carry disease-associated genetic variants at a high rate. Most of the variants were in MYH7 or MYPBC3 for HCM and TNNT2 or TNNI3 for RCM.
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40
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Burke MA, Cook SA, Seidman JG, Seidman CE. Clinical and Mechanistic Insights Into the Genetics of Cardiomyopathy. J Am Coll Cardiol 2017; 68:2871-2886. [PMID: 28007147 DOI: 10.1016/j.jacc.2016.08.079] [Citation(s) in RCA: 219] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 08/01/2016] [Accepted: 08/02/2016] [Indexed: 12/19/2022]
Abstract
Over the last quarter-century, there has been tremendous progress in genetics research that has defined molecular causes for cardiomyopathies. More than a thousand mutations have been identified in many genes with varying ontologies, therein indicating the diverse molecules and pathways that cause hypertrophic, dilated, restrictive, and arrhythmogenic cardiomyopathies. Translation of this research to the clinic via genetic testing can precisely group affected patients according to molecular etiology, and identify individuals without evidence of disease who are at high risk for developing cardiomyopathy. These advances provide insights into the earliest manifestations of cardiomyopathy and help to define the molecular pathophysiological basis for cardiac remodeling. Although these efforts remain incomplete, new genomic technologies and analytic strategies provide unparalleled opportunities to fully explore the genetic architecture of cardiomyopathies. Such data hold the promise that mutation-specific pathophysiology will uncover novel therapeutic targets, and herald the beginning of precision therapy for cardiomyopathy patients.
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Affiliation(s)
- Michael A Burke
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; Department of Genetics, Harvard Medical School, Boston, Massachusetts
| | - Stuart A Cook
- National Heart & Lung Institute, Imperial College London, London, United Kingdom; National Heart Centre Singapore, Singapore; Duke-National University of Singapore, Singapore
| | | | - Christine E Seidman
- Department of Genetics, Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland.
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42
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Abstract
Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease. © 2017 American Physiological Society. Compr Physiol 7:891-944, 2017.
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Affiliation(s)
- Christine A Henderson
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
| | - Christopher G Gomez
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
| | - Stefanie M Novak
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
| | - Lei Mi-Mi
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
| | - Carol C Gregorio
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona, USA.,Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, USA
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43
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Gu Q, Mendsaikhan U, Khuchua Z, Jones BC, Lu L, Towbin JA, Xu B, Purevjav E. Dissection of Z-disc myopalladin gene network involved in the development of restrictive cardiomyopathy using system genetics approach. World J Cardiol 2017; 9:320-331. [PMID: 28515850 PMCID: PMC5411966 DOI: 10.4330/wjc.v9.i4.320] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/09/2017] [Accepted: 02/28/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate the regulation of Myopalladin (Mypn) and identify its gene network involved in restrictive cardiomyopathy (RCM). METHODS Gene expression values were measured in the heart of a large family of BXD recombinant inbred (RI) mice derived from C57BL/6J and DBA/2J. The proteomics data were collected from Mypn knock-in and knock-out mice. Expression quantitative trait locus (eQTL) mapping methods and gene enrichment analysis were used to identify Mypn regulation, gene pathway and co-expression networks. RESULTS A wide range of variation was found in expression of Mypn among BXD strains. We identified upstream genetic loci at chromosome 1 and 5 that modulate the expression of Mypn. Candidate genes within these loci include Ncoa2, Vcpip1, Sgk3, and Lgi2. We also identified 15 sarcomeric genes interacting with Mypn and constructed the gene network. Two novel members of this network (Syne1 and Myom1) have been confirmed at the protein level. Several members in this network are already known to relate to cardiomyopathy with some novel genes candidates that could be involved in RCM. CONCLUSION Using systematic genetics approach, we constructed Mypn co-expression networks that define the biological process categories within which similarly regulated genes function. Through this strategy we have found several novel genes that interact with Mypn that may play an important role in the development of RCM.
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Affiliation(s)
- Qingqing Gu
- Qingqing Gu, Biao Xu, Department of Cardiology, Drum Tower Clinic Hospital, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
| | - Uzmee Mendsaikhan
- Qingqing Gu, Biao Xu, Department of Cardiology, Drum Tower Clinic Hospital, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
| | - Zaza Khuchua
- Qingqing Gu, Biao Xu, Department of Cardiology, Drum Tower Clinic Hospital, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
| | - Byron C Jones
- Qingqing Gu, Biao Xu, Department of Cardiology, Drum Tower Clinic Hospital, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
| | - Lu Lu
- Qingqing Gu, Biao Xu, Department of Cardiology, Drum Tower Clinic Hospital, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
| | - Jeffrey A Towbin
- Qingqing Gu, Biao Xu, Department of Cardiology, Drum Tower Clinic Hospital, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
| | - Biao Xu
- Qingqing Gu, Biao Xu, Department of Cardiology, Drum Tower Clinic Hospital, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
| | - Enkhsaikhan Purevjav
- Qingqing Gu, Biao Xu, Department of Cardiology, Drum Tower Clinic Hospital, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China
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Chen Y, Barajas-Martinez H, Zhu D, Wang X, Chen C, Zhuang R, Shi J, Wu X, Tao Y, Jin W, Wang X, Hu D. Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome. J Transl Med 2017; 15:78. [PMID: 28427417 PMCID: PMC5399316 DOI: 10.1186/s12967-017-1180-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 04/10/2017] [Indexed: 01/12/2023] Open
Abstract
Background Hypertrophic cardiomyopathy (HCM) patients with early repolarization (ER) pattern are at higher risk of ventricular arrhythmia, yet the genetic background of this situation has not been well investigated. Here we report novel trigenic mutations detected in a Chinese family of obstructive HCM with ER and short QT syndrome (SQTS). Methods Proband and family members underwent detailed medical assessments. DNAs were extracted from peripheral blood leukocytes for genetic screening with next generation method. The functional characterization of the mutation was conducted in TSA201 cells with patch-clamp experiment. Results The proband was a 52-year-old male who had a ER pattern ECG in inferioral-lateral leads with atrioventricular block and QTc of 356 ms. He also suffered from severe left ventricular hypertrophy and dysfunction. Targeted sequencing revealed trigenic mutations: c.700G>A/p.E234K in DES, c.2966G>A/p.R989H in MYPN, and c.5918G>C/p.R1973P in CACNA1C. All mutations were also detected in his daughter with ER and mild myocardium hypertrophy. The CACNA1C-R1973P mutation caused significant reduction (68.4%) of ICa compared to CACNA1C-WT (n = 14 and 14, P < 0.05). The computer modeling showed that all 3 mutations were highly disease-causing. The proband received the CRT-D (cardiac resynchronizing therapy) implantation, which lowered the left ventricular outflow tract gradient (LVOTG, 124 mmHg pre vs. 27 mmHg post) and restored the LV function (LVEF 40% pre vs. 63% post). Conclusions The study reveals a novel CACNA1C mutation underlying the unique ER pattern ECGs with SQTS. It also shows the rare trigenic mutations are the pathogenic substrates for the complicated clinical manifestation in HCM patients. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1180-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yanhong Chen
- Department of Cardiology, Wuhan Asia Heart Hospital, Wuhan University, Wuhan, 430022, China.,Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China
| | | | - Dongxiao Zhu
- Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China
| | - Xihui Wang
- Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China
| | - Chonghao Chen
- Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China
| | - Ruijuan Zhuang
- Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China
| | - Jingjing Shi
- Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China
| | - Xueming Wu
- Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China
| | - Yijia Tao
- Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China
| | - Weidong Jin
- Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China
| | - Xiaoyan Wang
- Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China.
| | - Dan Hu
- Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, 430060, China. .,Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY, 13501, USA. .,Molecular Genetics Department, SCRO Chair of Stem Cell Center, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY, 13501, USA.
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Lornage X, Malfatti E, Chéraud C, Schneider R, Biancalana V, Cuisset JM, Garibaldi M, Eymard B, Fardeau M, Boland A, Deleuze JF, Thompson J, Carlier RY, Böhm J, Romero NB, Laporte J. Recessive MYPN mutations cause cap myopathy with occasional nemaline rods. Ann Neurol 2017; 81:467-473. [PMID: 28220527 DOI: 10.1002/ana.24900] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 02/13/2017] [Accepted: 02/13/2017] [Indexed: 12/13/2022]
Abstract
Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.
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Affiliation(s)
- Xavière Lornage
- Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.,National Institute of Health and Medical Research, Illkirch, France.,National Center for Scientific Research, Illkirch, France.,Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch, France
| | - Edoardo Malfatti
- Sorbonne Universities, Pierre and Marie Curie University, National Institute of Health and Medical Research, National Center for Scientific Research, Center for Research in Myology, Pitié-Salpêtrière Hospital, Paris, France.,Unit of Neuromuscular Morphology, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.,Reference Center for Neuromuscular Pathology Paris-East, Institute of Myology, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France
| | - Chrystel Chéraud
- Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.,National Institute of Health and Medical Research, Illkirch, France.,National Center for Scientific Research, Illkirch, France.,Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch, France
| | - Raphaël Schneider
- Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.,National Institute of Health and Medical Research, Illkirch, France.,National Center for Scientific Research, Illkirch, France.,Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch, France.,Department of Computer Science, ICube, National Center for Scientific Research, Strasbourg, France
| | - Valérie Biancalana
- Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.,National Institute of Health and Medical Research, Illkirch, France.,National Center for Scientific Research, Illkirch, France.,Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch, France.,Diagnostic Genetic Laboratory, New Civil Hospital, Regional University Hospital Center, Strasbourg, France
| | - Jean-Marie Cuisset
- Department of Neuropediatrics, Reference Center for Neuromuscular Diseases, Roger-Salengro Hospital, Regional University Hospital Center, Lille, France
| | - Matteo Garibaldi
- Unit of Neuromuscular Morphology, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.,Unit of Neuromuscular Diseases, Department of Neurology, Mental Health, and Sensory Organs, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.,Neuromuscular Diseases Centre, Department of Clinical Neurosciences, University Hospital of Nice, Nice, France
| | - Bruno Eymard
- Sorbonne Universities, Pierre and Marie Curie University, National Institute of Health and Medical Research, National Center for Scientific Research, Center for Research in Myology, Pitié-Salpêtrière Hospital, Paris, France.,Reference Center for Neuromuscular Pathology Paris-East, Institute of Myology, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France
| | - Michel Fardeau
- Sorbonne Universities, Pierre and Marie Curie University, National Institute of Health and Medical Research, National Center for Scientific Research, Center for Research in Myology, Pitié-Salpêtrière Hospital, Paris, France.,Unit of Neuromuscular Morphology, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.,Reference Center for Neuromuscular Pathology Paris-East, Institute of Myology, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France
| | - Anne Boland
- National Genotyping Center, Genomics Institute, Office of Atomic Energy and Alternative Energies, Evry, France
| | - Jean-François Deleuze
- National Genotyping Center, Genomics Institute, Office of Atomic Energy and Alternative Energies, Evry, France
| | - Julie Thompson
- Department of Computer Science, ICube, National Center for Scientific Research, Strasbourg, France
| | - Robert-Yves Carlier
- Department of Radiology, Neurolocomotor Division, Raymond Poincaré Hospital, University Hospitals Paris-Ile-de-France West, Public Hospital Network of Paris, Garches, France.,Versailles Saint-Quentin-en-Yvelines University, Versailles, France
| | - Johann Böhm
- Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.,National Institute of Health and Medical Research, Illkirch, France.,National Center for Scientific Research, Illkirch, France.,Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch, France
| | - Norma B Romero
- Sorbonne Universities, Pierre and Marie Curie University, National Institute of Health and Medical Research, National Center for Scientific Research, Center for Research in Myology, Pitié-Salpêtrière Hospital, Paris, France.,Unit of Neuromuscular Morphology, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.,Reference Center for Neuromuscular Pathology Paris-East, Institute of Myology, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France
| | - Jocelyn Laporte
- Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.,National Institute of Health and Medical Research, Illkirch, France.,National Center for Scientific Research, Illkirch, France.,Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch, France
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Miyatake S, Mitsuhashi S, Hayashi YK, Purevjav E, Nishikawa A, Koshimizu E, Suzuki M, Yatabe K, Tanaka Y, Ogata K, Kuru S, Shiina M, Tsurusaki Y, Nakashima M, Mizuguchi T, Miyake N, Saitsu H, Ogata K, Kawai M, Towbin J, Nonaka I, Nishino I, Matsumoto N. Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy. Am J Hum Genet 2017; 100:169-178. [PMID: 28017374 PMCID: PMC5223057 DOI: 10.1016/j.ajhg.2016.11.017] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Accepted: 11/22/2016] [Indexed: 01/16/2023] Open
Abstract
Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.
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Affiliation(s)
- Satoko Miyatake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa 236-0004, Japan
| | - Satomi Mitsuhashi
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Department of Genome Medicine Development, Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Biomedical Informatics Laboratory, Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Yukiko K Hayashi
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Department of Pathophysiology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Enkhsaikhan Purevjav
- Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN 38103, USA
| | - Atsuko Nishikawa
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Department of Education, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan
| | - Eriko Koshimizu
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Mikiya Suzuki
- Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan
| | - Kana Yatabe
- Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan
| | - Yuzo Tanaka
- Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan
| | - Katsuhisa Ogata
- Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan
| | - Satoshi Kuru
- Department of Neurology, National Hospital Organization Suzuka National Hospital, Suzuka, Mie 513-8501, Japan
| | - Masaaki Shiina
- Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Yoshinori Tsurusaki
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Mitsuko Nakashima
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Takeshi Mizuguchi
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Noriko Miyake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Hirotomo Saitsu
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Kazuhiro Ogata
- Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Mitsuru Kawai
- Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan
| | - Jeffrey Towbin
- Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN 38103, USA
| | - Ikuya Nonaka
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan
| | - Ichizo Nishino
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan
| | - Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
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Wang X, Zhou K, Hua Y, Li Y. Approaching the facts between genetic mutation and clinical practice of hypertrophic cardiomyopathy: A case report with RAF1 770C>T mutant. Medicine (Baltimore) 2016; 95:e4815. [PMID: 27631234 PMCID: PMC5402577 DOI: 10.1097/md.0000000000004815] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION Hypertrophic cardiomyopathy (HCM) is one of the most common cardiomyopathies, which induces sudden cardiac death. Several mutants have been identified among HCM cases. METHODS AND RESULTS A 10-month female infant who experienced cough, fever, aggressive exertional dyspnea, and recurrent cyanosis was admitted to our hospital. The patient was first diagnosed with type I respiratory failure, dysfunction of heart, severe pneumonia, and also some cardiac disorders were suspected. The echocardiography, cardiac computed tomography scan, cardiac magnetic resonance imaging scan, and also electrocardiogram were performed to confirm a diagnosis of HCM. Moreover, the whole-genome sequencing and chromatin analysis have been suggested. Based on the sequencing analysis, a new heterozygous mutant of RAF1 at c. 770C>T had been identified in absence of the same mutant in both her parents. Besides, the existence of normal karyotypes was confirmed among 3 samples. CONCLUSION So we first reported a single mutant of RAF1 770C>T with idiopathic HCM in a very early age. This patient would have suffered significant cardiac ventricular hypertrophy with more severe clinical manifestation in an extremely younger age compared with other identified mutations. However, we could only take limited advantages of deoxyribonucleic acid sequencing in HCM diagnosis and therapy. Reporting additional observations of well designed cohorts with a long-term follow-up would be very helpful to accelerate the transition of genetic molecular research on HCM.
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Affiliation(s)
- Xiaoqin Wang
- Department of Pediatrics
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects
| | - Kaiyu Zhou
- Department of Pediatrics
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects
- Program for Changjiang Scholars and Innovative Research Team in University, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yimin Hua
- Department of Pediatrics
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects
- Program for Changjiang Scholars and Innovative Research Team in University, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Correspondence: Yimin Hua, Department of Pediatrics, West China Second University Hospital, Sichuan University No. 20, 3rd Section, South Renmin Road, Chengdu 610041, China (e-mail: ); Yifei Li, Department of Pediatrics, West China Second University Hospital, Sichuan University No. 20, 3rd Section, South Renmin Road, Chengdu 610041, China (e-mail: )
| | - Yifei Li
- Department of Pediatrics
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects
- Correspondence: Yimin Hua, Department of Pediatrics, West China Second University Hospital, Sichuan University No. 20, 3rd Section, South Renmin Road, Chengdu 610041, China (e-mail: ); Yifei Li, Department of Pediatrics, West China Second University Hospital, Sichuan University No. 20, 3rd Section, South Renmin Road, Chengdu 610041, China (e-mail: )
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48
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Li S, Mo K, Tian H, Chu C, Sun S, Tian L, Ding S, Li TR, Wu X, Liu F, Zhang Z, Xu T, Sun LV. Lmod2 piggyBac mutant mice exhibit dilated cardiomyopathy. Cell Biosci 2016; 6:38. [PMID: 27274810 PMCID: PMC4893230 DOI: 10.1186/s13578-016-0101-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 05/03/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Leiomodin proteins, Lmod1, Lmod2 and Lmod3, are key regulators of the thin filament length in muscles. While Lmod1 is specifically expressed in smooth muscles, both Lmod2 and Lmod3 are expressed in striated muscles including both cardiac and skeletal muscles. We and others have previously shown that Lmod3 mainly function in skeletal muscles and the mutant mice display disorganized sarcomere. Lmod2 protein has been found to act as an actin filament nucleator in both cell-free assays and in cultured rat and chicken cardiomyocytes. RESULTS To better understand the function of Lmod2 in vivo, we have identified and characterized a piggyBac (PB) insertional mouse mutant. Our analysis revealed that the PB transposon inserts in the first exon of the Lmod2 gene and severely disrupts its expression. We found that Lmod2 (PB/PB) mice exhibit typical dilated cardiomyopathy (DCM) with ventricular arrhythmias and postnatal lethality. Electron microscope reveals that the Lmod2 (PB/PB) hearts carry disordered sarcomere, disarrayed thin filaments, and distorted intercalated discs (ICDs). Those ICDs display not only decreased convolutions, but also reduced electron-dense staining, indicating less ICDs component proteins in Lmod2 (PB/PB) hearts. Consistent with the phenotype, the expression of the ICD component genes, β-catenin and Connexin43, are down-regulated. CONCLUSIONS Taken together, our data reveal that Lmod2 is required in heart thin filaments for integrity of sarcomere and ICD and deficient mice exhibit DCM with ventricular arrhythmias and postnatal lethality. The Lmod2 (PB/PB) mutant offers a valuable resource for interrogation of pathogenesis and development of therapeutics for DCM.
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Affiliation(s)
- Shuang Li
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Kaiqi Mo
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Hong Tian
- Cardiac Center, Children's Hospital of Fudan University, Shanghai, China
| | - Chen Chu
- Cardiac Center, Children's Hospital of Fudan University, Shanghai, China
| | - Shuna Sun
- Cardiac Center, Children's Hospital of Fudan University, Shanghai, China
| | - Lei Tian
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China ; Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT USA
| | - Sheng Ding
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China ; Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT USA
| | - Tong-Ruei Li
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Xiaohui Wu
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Fang Liu
- Cardiac Center, Children's Hospital of Fudan University, Shanghai, China
| | - Zhen Zhang
- Shanghai Pediatric Congenital Heart Institute, Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Tian Xu
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China ; Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT USA
| | - Ling V Sun
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China
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49
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Bang ML. Animal Models of Congenital Cardiomyopathies Associated With Mutations in Z-Line Proteins. J Cell Physiol 2016; 232:38-52. [PMID: 27171814 DOI: 10.1002/jcp.25424] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/10/2016] [Indexed: 01/15/2023]
Abstract
The cardiac Z-line at the boundary between sarcomeres is a multiprotein complex connecting the contractile apparatus with the cytoskeleton and the extracellular matrix. The Z-line is important for efficient force generation and transmission as well as the maintenance of structural stability and integrity. Furthermore, it is a nodal point for intracellular signaling, in particular mechanosensing and mechanotransduction. Mutations in various genes encoding Z-line proteins have been associated with different cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, and left ventricular noncompaction, and mutations even within the same gene can cause widely different pathologies. Animal models have contributed to a great advancement in the understanding of the physiological function of Z-line proteins and the pathways leading from mutations in Z-line proteins to cardiomyopathy, although genotype-phenotype prediction remains a great challenge. This review presents an overview of the currently available animal models for Z-line and Z-line associated proteins involved in human cardiomyopathies with special emphasis on knock-in and transgenic mouse models recapitulating the clinical phenotypes of human cardiomyopathy patients carrying mutations in Z-line proteins. Pros and cons of mouse models will be discussed and a future outlook will be given. J. Cell. Physiol. 232: 38-52, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Marie-Louise Bang
- Institute of Genetic and Biomedical Research, UOS Milan, National Research Council and Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
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50
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Yu HC, Coughlin CR, Geiger EA, Salvador BJ, Elias ER, Cavanaugh JL, Chatfield KC, Miyamoto SD, Shaikh TH. Discovery of a potentially deleterious variant in TMEM87B in a patient with a hemizygous 2q13 microdeletion suggests a recessive condition characterized by congenital heart disease and restrictive cardiomyopathy. Cold Spring Harb Mol Case Stud 2016; 2:a000844. [PMID: 27148590 PMCID: PMC4853521 DOI: 10.1101/mcs.a000844] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/03/2016] [Indexed: 01/22/2023] Open
Abstract
Restrictive cardiomyopathy (RCM) is a rare cause of heart muscle disease with the highest mortality rate among cardiomyopathy types. The etiology of RCM is poorly understood, although genetic causes have been implicated, and syndromic associations have been described. Here, we describe a patient with an atrial septal defect and restrictive cardiomyopathy along with craniofacial anomalies and intellectual disabilities. Initial screening using chromosomal microarray analysis (CMA) identified a maternally inherited 2q13 microdeletion. The patient had many of the features reported in previous cases with the recurrent 2q13 microdeletion syndrome. However, the inheritance of the microdeletion from an unaffected mother combined with the low incidence (10%) and milder forms of cardiac defects in previously reported cases made the clinical significance of the CMA results unclear. Whole-exome sequencing (WES) with trio-based analysis was performed and identified a paternally inherited TMEM87B mutation (c.1366A>G, p.Asn456Asp) in the patient. TMEM87B, a highly conserved, transmembrane protein of currently unknown function, lies within the critical region of the recurrent 2q13 microdeletion syndrome. Furthermore, a recent study had demonstrated that depletion of TMEM87B in zebrafish embryos affected cardiac development and led to cardiac hypoplasia. Thus, by combining CMA and WES, we potentially uncover an autosomal-recessive disorder characterized by a severe cardiac phenotype caused by mutations in TMEM87B. This study expands the spectrum of phenotypes associated with the recurrent 2q13 microdeletion syndrome and also further suggests the role of TMEM87B in its etiology, especially the cardiac pathology.
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Affiliation(s)
- Hung-Chun Yu
- Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Curtis R Coughlin
- Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Elizabeth A Geiger
- Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Blake J Salvador
- Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Ellen R Elias
- Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Jean L Cavanaugh
- Department of Pediatrics, Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Kathryn C Chatfield
- Department of Pediatrics, Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Shelley D Miyamoto
- Department of Pediatrics, Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Tamim H Shaikh
- Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA;; Colorado Intellectual and Developmental Disabilities Research Center (IDDRC), University of Colorado School of Medicine, Aurora, Colorado 80045, USA
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