GATA4 – Dilated Cardiomyopathy

GATA4 is a zinc-finger transcription factor essential for cardiac morphogenesis, regulating genes involved in cardiomyocyte differentiation and function. Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and systolic dysfunction, leading to heart failure and increased transplant risk. Variants in GATA4 have been reported in both familial and sporadic DCM cohorts, supporting a role in disease pathogenesis.

Autosomal dominant inheritance of DCM has been documented in a family carrying a heterozygous GATA4 missense mutation, p.Cys271Ser, which co-segregates with disease and is absent in 200 controls (PMID:24041700). In a separate study of 220 unrelated sporadic DCM patients, three novel heterozygous missense variants—c.115G>T (p.Val39Leu), c.679C>A (p.Pro226Gln) and c.835A>T (p.Thr279Ser)—were identified in three probands, giving a mutational prevalence of ~1.36% (PMID:25017055).

Segregation analysis in the p.Cys271Ser family demonstrated complete penetrance among affected relatives, confirming the variant’s pathogenicity (PMID:24041700). All four missense variants were absent from over 400 ethnically matched control chromosomes and affect amino acids conserved across vertebrates.

Functional assays using luciferase reporter systems revealed that p.Cys271Ser, p.Val39Leu, p.Pro226Gln and p.Thr279Ser each exhibit significantly decreased transcriptional activity and markedly reduced synergistic activation with NKX2-5, consistent with a haploinsufficiency mechanism (PMID:25017055; PMID:24041700).

No studies to date have reported conflicting evidence for GATA4 in DCM. The concordance of genetic segregation and functional LoF effects underpins the clinical validity of GATA4 testing in patients with DCM.

Key Take-home: Heterozygous missense variants in GATA4 cause autosomal dominant dilated cardiomyopathy via loss of transcriptional function, supporting its use in diagnostic genetic panels.

References

• Biochemical and biophysical research communications • 2013 • GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy. PMID:24041700
• Gene • 2014 • Prevalence and spectrum of GATA4 mutations associated with sporadic dilated cardiomyopathy. PMID:25017055

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