GATA5 loss-of-function mutation in familial dilated cardiomyopathy

Abstract

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.

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

“…Notably, loss-of-function mutations in several transcriptional cooperative partners of TBX20, including NKX2-5, GATA4, GATA5, GATA6 and TBX5, have been associated with DCM in humans [26][27][28][29][30][31][32]. Hence, dysfunctional TBX20 may confer enhanced susceptibility to DCM probably by reducing synergistic activation of some target genes essential for embryonic cardiogenesis and adult cardiac structure and function.…”

“…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]. Considering that the expression profile and functional characteristics of the TBX20 overlap at least in part with those of NKX2-5, GATA4, GATA5, GATA6 and TBX5 [33][34][35], it is justified to make the hypothesis that genetically defective TBX20 may predispose to DCM in a subgroup of patients.…”

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

“…In humans, mutations in GATA5 have been shown to lead to a variety of CHDs that may reflect endocardially or myocardially based defects. They include septal defects (ASDs and VSDs), BAV, DORV, pulmonary stenosis, and cardiomyopathies [36][37][38] (Figure 1 and Table 2). A role for GATA5 as a susceptibility gene for human hypertension due to endothelial dysregulation was also described.…”

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

“…8,[10][11][12][13][14][15][16][17][18][19][20] Although we made a genetic analysis of several cardiac core transcriptional factor genes in the two mutation carriers with DCM, including GATA4, GATA5, GATA6, TBX5, TBX20, and HAND1, as described previously, [22][23][24][25][26][27][28][29][30][31] and found no mutations, we cannot rule out the possibility that the genetic variants in other genes may also contribute to DCM in these two patients. Genome sequencing analysis may help to explain the possibility for these patients.…”

“…[22][23][24][25][26][27][28][29][30][31] More interestingly, mutations in NKX2-5, another cardiac key transcriptional factor, have been found to be responsible for familial adult-onset DCM, 32,33) which makes it justifiable to evaluate the prevalence and spectrum of NKX2-5 mutations in the patients with sporadic adult-onset DCM.…”