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HAND2 loss-of-function mutation causes familial dilated cardiomyopathy

Published on Sep 1, 2019in European Journal of Medical Genetics2.022
· DOI :10.1016/j.ejmg.2018.09.007
Hua Liu9
Estimated H-index: 9
(SJTU: Shanghai Jiao Tong University),
Ying-Jia Xu3
Estimated H-index: 3
(Fudan University)
+ 8 AuthorsYi-Qing Yang5
Estimated H-index: 5
(Fudan University)
Abstract
Abstract As two members of the basic helix-loop-helix family of transcription factors, HAND1 and HAND2 are both required for the embryonic cardiogenesis and postnatal ventricular structural remodeling. Recently a HAND1 mutation has been reported to cause dilated cardiomyopathy (DCM). However, the association of a HAND2 mutation with DCM is still to be ascertained. In this research, the coding regions and splicing junction sites of the HAND2 gene were sequenced in 206 unrelated patients affected with idiopathic DCM, and a new heterozygous HAND2 mutation, NM_021973.2: c.199G > T; p.(Glu67*), was discovered in an index patient with DCM. The nonsense mutation was absent in 300 unrelated, ethnically-matched healthy persons. Genetic scan of the mutation carrier's family members revealed that the genetic mutation co-segregated with DCM, which was transmitted in an autosomal dominant fashion, with complete penetrance. Functional deciphers unveiled that the mutant HAND2 protein had no transcriptional activity. In addition, the mutation abrogated the synergistic transcriptional activation between HAND2 and GATA4 or between HAND2 and NKX2.5, two other cardiac transcription factors that have been implicated in DCM. These research findings firstly suggest HAND2 as a novel gene predisposing to DCM in humans, which adds novel insight to the molecular pathogenesis of DCM, implying potential implications in the design of personized preventive and therapeutic strategies against DCM.
  • References (63)
  • Citations (3)
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References63
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#1Alexandre Janin (University of Lyon)H-Index: 5
#2Karine NguyenH-Index: 15
Last. Gilles Millat (University of Lyon)H-Index: 16
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Dilated Cardiomyopathy (DCM) is one of the leading causes of heart failure with high morbidity and mortality. More than 40 genes have been reported to cause DCM. To provide new insights into the pathophysiology of dilated cardiomyopathy, a NGS workflow based on a panel of 48 cardiomyopathies-causing genes was used to analyze a cohort of 222 DCM patients. Truncating variants were detected on 63 unrelated DCM cases (28.4%). Most of them were identified, as expected, on TTN (29 DCM probands), but t...
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#1David Higgins (UW: University of Washington)H-Index: 1
#2Jessica Otero (UW: University of Washington)H-Index: 1
Last. Yuk M. Law (UW: University of Washington)H-Index: 19
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Iron deficiency (FeD), with or without anemia, in adults with heart failure (HF) is associated with poor outcomes, which can be improved with replacement therapy. A similar therapeutic opportunity may exist for children; however, iron laboratory measurements and FeD have not been described in pediatric patients with HF. A single-center, retrospective study was conducted on 28 patients
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#1Matteo Dal FerroH-Index: 8
#2Davide StolfoH-Index: 13
Last. Gianfranco SinagraH-Index: 42
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Objective To explore the genetic landscape of a well selected dilated cardiomyopathy (DCM) cohort, assessing the possible relation between different genotypes and left ventricular reverse remodelling (LVRR). Methods A cohort of 152 patients with DCM from the Heart Muscle Disease Registry of Trieste has been studied by next-generation sequencing (NGS). Patients were grouped into different ‘gene-clusters’ with functionally homogeneous genetic backgrounds. LVRR was defined by left ventricular eject...
22 CitationsSource
#1Konstantinos C. Siontis (UM: University of Michigan)H-Index: 17
#2H. Myra Kim (UM: University of Michigan)H-Index: 46
Last. Frank Bogun (UM: University of Michigan)H-Index: 60
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Background Knowledge of complex arrhythmogenic substrates can help plan ventricular tachycardia (VT) ablation in patients with idiopathic dilated cardiomyopathy (DCM). Objective The purpose of this study was to assess whether preprocedural late gadolinium enhancement magnetic resonance imaging (LGE-MRI) can improve ablation outcomes in DCM. Methods Consecutive patients (N = 96) with idiopathic DCM underwent VT ablation with open-irrigated catheters (2006–2016). Before 2012, LGE-MRI was not perfo...
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#2Luisa Mestroni (Anschutz Medical Campus)H-Index: 40
Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review...
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#1Evmorfia Petropoulou (St George's, University of London)H-Index: 3
Last. Yalda Jamshidi (St George's, University of London)H-Index: 24
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Abstract Familial dilated cardiomyopathy (DCM) is characterized by ventricular dilation and depressed myocardial performance. It is a genetically heterogeneous disorder associated with mutations in over 60 genes. We carried out whole exome sequencing in combination with cardiomyopathy-related gene-filtering on two affected family members to identify the possible causative mutation in a consanguineous Iranian family with DCM. Two novel variants in cardiomyopathy-related genes were identified: c.2...
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#1Pamela A. Long (Mayo Clinic)H-Index: 7
#2Jeanne L. TheisH-Index: 9
Last. Timothy Mark Olson (Mayo Clinic)H-Index: 33
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: Non-ischemic dilated cardiomyopathy (DCM) has been recognized as a heritable disorder for over 25 years, yet clinical genetic testing is non-diagnostic in >50% of patients, underscoring the ongoing need for DCM gene discovery. Here, whole exome sequencing uncovered a novel molecular basis for idiopathic end-stage heart failure in two sisters who underwent cardiac transplantation at three years of age. Compound heterozygous recessive mutations in TAF1A, encoding an RNA polymerase I complex prot...
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#1Hai-Xin YuanH-Index: 2
#2Kai YanH-Index: 1
Last. Lin ZhangH-Index: 9
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: Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation, and is associated with systolic dysfunction and increased action potential duration. Approximately 50% of DCM cases are caused by inherited gene mutations with genetic and phenotypic heterogeneity. Next generation sequencing may be useful in screening unknown mutations in such cases.A family was identified with DCM, in which the affected family members developed heart failure, arrhythmia, and sudden death. Probands and...
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#1Joshua W. Vincentz (IU: Indiana University)H-Index: 6
#2Kevin P. Toolan (IU: Indiana University)H-Index: 2
Last. Anthony B. FirulliH-Index: 33
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Coordinated cardiomyocyte growth, differentiation, and morphogenesis are essential for heart formation. We demonstrate that the bHLH transcription factors Hand1 and Hand2 play critical regulatory roles for left ventricle (LV) cardiomyocyte proliferation and morphogenesis. Using an LV-specific Cre allele (Hand1LV-Cre), we ablate Hand1-lineage cardiomyocytes, revealing that DTA-mediated cardiomyocyte death results in a hypoplastic LV by E10.5. Once Hand1-linage cells are removed from the LV, and H...
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Abstract As a prevalent primary myocardial disease, dilated cardiomyopathy (DCM) represents the most common cause of heart failure in the young and the most frequent indication for cardiac transplantation. Aggregating evidence highlights the genetic basis of DCM. However, due to substantial genetic heterogeneity, the genetic defects of DCM in most cases remain elusive. In the current investigation, the entire coding exons and splicing junctions of the KLF5 gene, which encodes a key transcription...
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#1Ana S. A. Cohen (ISMMS: Icahn School of Medicine at Mount Sinai)
Last. Ram Singh (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 1
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Congenital heart defects (CHDs) are caused by a disruption in heart morphogenesis, which is dependent, in part, on a network of transcription factors (TFs) that regulate myocardial development. Heterozygous sequence variants in the basic helix-loop-helix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene. We report a 31-month-old male with unicommissural unicuspid...
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#1Rowida AlmomaniH-Index: 10
#2Johanna C. Herkert (UMCG: University Medical Center Groningen)H-Index: 13
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Background Idiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. Identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. In this study, we sought to identify the underlying genetic defect in a patient born to consanguineous parents with rapidly progressive DCM that led to deat...
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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 d...
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