HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy

2016 ◽  
Vol 54 (7) ◽  
Author(s):  
Yi-Meng Zhou ◽  
Xiao-Yong Dai ◽  
Xing-Biao Qiu ◽  
Fang Yuan ◽  
Ruo-Gu Li ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Loss Of Function ◽  
Coding Region ◽  
Helix Loop Helix ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Synergistic Activation

AbstractThe basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown.The whole coding region and splicing junctions of theA novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM.This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM.

MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy

2018 ◽  
Vol 56 (3) ◽  
pp. 502-511 ◽  
Author(s):  
Fang Yuan ◽  
Zhao-Hui Qiu ◽  
Xing-Hua Wang ◽  
Yu-Min Sun ◽  
Jun Wang ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Index Patient ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Wild Type Counterpart ◽  
New Gene ◽  
Close Relatives

AbstractBackground:The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of theMEF2Cgene results in dilated cardiomyopathy (DCM). However, in humans, the association ofMEF2Cvariation with DCM remains to be investigated.Methods:The coding regions and splicing boundaries of theMEF2Cgene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identifiedMEF2Cmutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped forMEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.Results:A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier’s family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM.Conclusions:This study indicatesMEF2Cas a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.

TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy

2016 ◽  
Vol 54 (2) ◽  
Author(s):  
Cui-Mei Zhao ◽  
Bing-Sun ◽  
Hao-Ming Song ◽  
Juan Wang ◽  
Wen-Jun Xu ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Loss Of Function ◽  
Coding Regions ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Genetic Components ◽  
Synergistic Activation ◽  
Autosomal Dominant Fashion ◽  
The Family ◽  
First Time

AbstractDilated cardiomyopathy (DCM) is a major cause of congestive heart failure, sudden cardiac death and cardiac transplantation. Aggregating evidence highlights the genetic origin of DCM. However, DCM is a genetically heterogeneous disorder, and the genetic components underlying DCM in most cases remain unknown.The coding regions and splicing junction sites of theA novel heterozygous TBX20 mutation, p.F256I, was identified in a family with DCM transmitted in an autosomal dominant fashion, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 600 control chromosomes and the altered amino acid was completely conserved evolutionarily among various species. Functional assays revealed that the mutant TBX20 had significantly diminished transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation of TBX20 with NKX2-5 or GATA4.This study links TBX20 loss-of-function mutation to idiopathic DCM in humans for the first time, providing novel insight into the molecular mechanism underpinning DCM.

CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy

2017 ◽  
Vol 55 (9) ◽  
Author(s):  
Xing-Biao Qiu ◽  
Xin-Kai Qu ◽  
Ruo-Gu Li ◽  
Hua Liu ◽  
Ying-Jia Xu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Autosomal Dominant ◽  
Cardiac Development ◽  
Index Patient ◽  
Loss Of Function ◽  
Zinc Finger Transcription Factor ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Postnatal Adaptation

AbstractBackground:The zinc finger transcription factor CASZ1 plays a key role in cardiac development and postnatal adaptation, and in mice, deletion of theMethods:The coding exons and splicing junction sites of theResults:A novel heterozygous CASZ1 mutation, p.K351X, was identified in an index patient with DCM. Genetic analysis of the mutation carrier’s family showed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 referential chromosomes, altered the amino acid that was highly conserved evolutionarily. Biological investigations revealed that the mutant CASZ1 had no transcriptional activity.Conclusions:The current study reveals

ZBTB17 loss-of-function mutation contributes to familial dilated cardiomyopathy

2018 ◽  
Vol 33 (7) ◽  
pp. 722-732 ◽  
Author(s):  
Yu-Min Sun ◽  
Jun Wang ◽  
Ying-Jia Xu ◽  
Xin-Hua Wang ◽  
Fang Yuan ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Loss Of Function ◽  
Familial Dilated Cardiomyopathy

From molecular mechanisms of cardiac development to genetic substrate of congenital heart diseases

2010 ◽  
Vol 6 (3) ◽  
pp. 373-393 ◽  
Author(s):  
Antonella Cecchetto ◽  
Alessandra Rampazzo ◽  
Annalisa Angelini ◽  
Lucia Dal Bianco ◽  
Massimo Padalino ◽  
...  
Keyword(s):  
Congenital Heart ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Congenital Heart Diseases

scholarly journals A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias

2014 ◽  
Vol 35 (2) ◽  
pp. 478-486 ◽  
Author(s):  
FANG YUAN ◽  
XING-BIAO QIU ◽  
RUO-GU LI ◽  
XIN-KAI QU ◽  
JUAN WANG ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Loss Of Function ◽  
Familial Dilated Cardiomyopathy

scholarly journals Misregulation of SDF1-CXCR4 Signaling Impairs Early Cardiac Neural Crest Cell Migration Leading to Conotruncal Defects

2013 ◽  
Vol 113 (5) ◽  
pp. 505-516 ◽  
Author(s):  
Sophie Escot ◽  
Cédrine Blavet ◽  
Sonja Härtle ◽  
Jean-Loup Duband ◽  
Claire Fournier-Thibault
Keyword(s):  
Neural Crest ◽  
Molecular Mechanisms ◽  
Heart Diseases ◽  
Smooth Muscles ◽  
Neural Crest Cell ◽  
Cell Types ◽  
Ventricular Septum ◽  
Embryonic Cells ◽  
Loss Of Function ◽  
Cardiac Neural Crest

Rationale: Cardiac neural crest cells (NCs) contribute to heart morphogenesis by giving rise to a variety of cell types from mesenchyme of the outflow tract, ventricular septum, and semilunar valves to neurons of the cardiac ganglia and smooth muscles of the great arteries. Failure in cardiac NC development results in outflow and ventricular septation defects commonly observed in congenital heart diseases. Cardiac NCs derive from the vagal neural tube, which also gives rise to enteric NCs that colonize the gut; however, so far, molecular mechanisms segregating these 2 populations and driving cardiac NC migration toward the heart have remained elusive. Objective: Stromal-derived factor-1 (SDF1) is a chemokine that mediates oriented migration of multiple embryonic cells and mice deficient for Sdf1 or its receptors, Cxcr4 and Cxcr7 , exhibit ventricular septum defects, raising the possibility that SDF1 might selectively drive cardiac NC migration toward the heart via a chemotactic mechanism. Methods and Results : We show in the chick embryo that Sdf1 expression is tightly coordinated with the progression of cardiac NCs expressing Cxcr4 . Cxcr4 loss-of-function causes delayed migration and enhanced death of cardiac NCs, whereas Sdf1 misexpression results in their diversion from their normal pathway, indicating that SDF1 acts as a chemoattractant for cardiac NCs. These alterations of SDF1 signaling result in severe cardiovascular defects. Conclusions: These data identify Sdf1 and its receptor Cxcr4 as candidate genes responsible for cardiac congenital pathologies in human.

scholarly journals GATA5 loss-of-function mutation in familial dilated cardiomyopathy

2014 ◽  
Vol 35 (3) ◽  
pp. 763-770 ◽  
Author(s):  
XIAN-LING ZHANG ◽  
NENG DAI ◽  
KAI TANG ◽  
YAN-QING CHEN ◽  
WEI CHEN ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Loss Of Function ◽  
Familial Dilated Cardiomyopathy

Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Qi Qiao ◽  
Cui-Mei Zhao ◽  
Chen-Xi Yang ◽  
Jia-Ning Gu ◽  
Yu-Han Guo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dilated Cardiomyopathy ◽  
Sanger Sequencing ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Functional Characterization ◽  
Luciferase Assay ◽  
Chinese Family ◽  
Sequencing Analysis ◽  
Loss Of Function

AbstractObjectivesDilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive.MethodsWhole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system.ResultsA heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM.ConclusionsThe findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients.

scholarly journals Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245681
Author(s):  
Juha W. Koskenvuo ◽  
Inka Saarinen ◽  
Saija Ahonen ◽  
Johanna Tommiska ◽  
Sini Weckström ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Molecular Diagnosis ◽  
Reference Population ◽  
Control Group ◽  
Loss Of Function ◽  
Familial Dilated Cardiomyopathy ◽  
Anchoring Protein ◽  
And Control ◽  
Cardiac Group

Background Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM. Methods and results We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, p<0.0001). Based on the frequency of NRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases. Conclusion Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.

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