GATA4 loss-of-function mutations in familial atrial fibrillation

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major source of the substantially increased morbidity and mortality. Growing studies demonstrate that genetic defects play pivotal roles in a subgroup of AF. However, AF is a genetically heterogeneous disorder and the molecular basis of AF in a majority of cases remains unknown.

Methods: The whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was analyzed in 130 unrelated probands with AF in contrast to 200 unrelated ethnically matched healthy individuals used as controls. The available family members of the probands harboring the identified mutations were genotyped. The functional effect of the mutant GATA4 was characterized using a luciferase reporter assay system.

Results: Two novel heterozygous GATA4 mutations, p.S70T and p.S160T, were identified in 2 unrelated families with AF inherited as an autosomal dominant trait, respectively, which co-segregated with AF in each family with complete penetrance. Functional analysis showed that the mutations of GATA4 were associated with a significantly decreased transcriptional activity.

Conclusion: The findings provide new insight into the molecular mechanism involved in the pathogenesis of AF, suggesting the potential implications in the genetic diagnosis and gene-specific therapy of this common arrhythmia.