Somatic GATA5 mutations in sporadic tetralogy of Fallot

Huang, Ruixuan; Xue, Song; Xu, Ying‐Jia; Zhou, Min; Yang, Yi‐Qing

doi:10.3892/ijmm.2014.1674

Cited by 26 publications

(13 citation statements)

References 69 publications

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“…In humans, a great number of GATA5 mutations have been previously associated with various congenital cardiovascular deformities, including atrial septal defect, ventricular septal defect, tetralogy of Fallot, double outlet right ventricle, aortic stenosis, patent ductus arteriosus and bicuspid aortic valve (40)(41)(42)(43)(44). In the present study, all the mutation carriers had DCM, but only 2 mutation carriers also had ventricular septal defect.…”

Section: Discussionsupporting

confidence: 49%

GATA5 loss-of-function mutation in familial dilated cardiomyopathy

Zhang

Tang

Chen

et al. 2014

International Journal of Molecular Medicine

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Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is an important cause of sudden cardiac death and heart failure and is the leading indication for heart transplantation in children and adults worldwide. Recent studies have revealed a strong genetic basis for idiopathic DCM, with many distinct genes causally implicated. Nevertheless, DCM is a genetically heterogeneous disorder and the genetic determinants underlying DCM in a substantial proportion of patients remain unclear. In this study, the whole coding exons and flanking introns of the GATA binding protein 5 (GATA5) gene, which codes for a zinc-finger transcription factor essential for cardiovascular development and structural remodeling, were sequenced in 130 unrelated patients with idiopathic DCM. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as the controls were genotyped for GATA5. The functional characteristics of the mutant GATA5 were analyzed in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.G240D, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily across species. Functional analyses revealed that the GATA5 mutant was associated with significantly diminished transcriptional activity. This study firstly links GATA5 mutation to DCM, which provides novel insight into the molecular mechanisms of DCM, suggesting a potential molecular target for the prenatal prophylaxis and allele-specific treatment of DCM.

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Section: Discussionsupporting

confidence: 49%

GATA5 loss-of-function mutation in familial dilated cardiomyopathy

Zhang

Tang

Chen

et al. 2014

International Journal of Molecular Medicine

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“…The human cardiac full-length cDNA was prepared as previously described (22,23,(36)(37)(38). Human HAND2 harboring the whole coding region was generated by PCR with the human heart cDNA as a template, cut with the restriction enzymes, EcoRI and NotI, and then subcloned at the EcoRI-NotI sites of the pcDNA3.1 vector (Invitrogen, Carlsbad, CA, USA).…”

Section: Expression Plasmids and Site-directed Mutagenesismentioning

confidence: 99%

“…Cardiogenesis from the early embryo to the formation of a fully functional four-chambered heart is a complex and dynamic process that necessitates a harmonious concerto of transcription factors, adhesion molecules, ion channels, signaling molecules and structural proteins, and both environmental and genetic risk factors may disrupt this biological process of heart development, resulting in a wide variety of CHDs (12). Although environmental exposures are also relevant, a growing number of studies have demonstrated that genetic defects are the leading cause of CHD, and thus far, mutations in >60 genes have been causally linked to CHD (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Among these CHD-causative genes, those encoding cardiac transcription factors, including homeodomain-containing protein, NK2 homeobox 5 (NKX2.5), GATA-binding protein 4 (GATA4) and T-box transcription factor 5 (TBX5), are the most commonly involved genes in the pathogenesis of CHD, underscoring the pivotal roles of cardiac transcription factors in cardiovascular development and disease (26).…”

Section: Introductionmentioning

confidence: 99%

A novel HAND2 loss-of-function mutation responsible for tetralogy of Fallot

Lü

Gong

Liu

et al. 2015

International Journal of Molecular Medicine

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Congenital heart disease (CHD), the most common type of developmental abnormality, is associated with substantial morbidity and mortality in humans worldwide. The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed 2 (HAND2), has been demonstrated to be crucial for normal cardiovascular development in animal models. However, whether a genetically defective HAND2 contributes to congenital heart disease (CHD) in humans remains to be explored. In this study, the entire coding region and splicing boundaries of the HAND2 gene were sequenced in a cohort of 145 unrelated patients with CHD. A total of 200 unrelated, ethnically-matched healthy individuals used as controls were also genotyped for HAND2. The functional effect of the mutant HAND2 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous HAND2 mutation, p.L47P, was identified in a patient with tetralogy of Fallot (TOF). The misense mutation, which altered the amino acid conserved evolutionarily among species, was absent in 400 control chromosomes. Functional analyses unveiled that the mutant HAND2 had a significantly decreased transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation between HAND2 and GATA4 or NKX2.5, other two cardiac key transcription factors involved in the pathogenesis of CHD. To the best of our knowledge, this study is the first to report the association of a HAND2 loss-of-function mutation with an increased vulnerability to TOF in humans, which provides novel insight into the molecular mechanism underpinning CHD, suggesting potential implications for the genetic counseling of families with CHD.

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“…As a part of a conserved regulatory network, these core cardiac transcription factors physically interact with each other to finely regulate cardiac development and structural remodeling [6][7][8]. Therefore, it is not surprising that an increasing number of mutations in these core cardiac transcription factors, especially for the most extensively investigated NKX2-5, GATA4, GATA5, GATA6, TBX5, and TBX20, have been identified in patients with various CHDs or cardiac arrhythmias [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. More interestingly, mutations in some cardiac transcription factors, such as NKX2-5, GATA4, GATA5, GATA6 and TBX5, have also been associated with isolated DCM in humans [26][27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%