Novel GATA6 loss-of-function mutation responsible for familial atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most commonly sustained cardiac arrhythmia, and confers a substantially increased risk of morbidity and mortality. Increasing evidence has indicated that hereditary defects are implicated in AF. However, AF is genetically heterogeneous and the genetic etiology of AF in a significant portion of patients remains unclear. In this study, the entire coding sequence and splice junctions of the GATA6 gene, which encodes a zinc-finger transcription factor crucial for cardiogenesis, were sequenced in 140 unrelated patients with lone AF. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically-matched healthy individuals used as the controls were genotyped. The functional characteristics of the mutant GATA6 were assessed in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA6 mutation, p.G469V, was identified in a family with AF inherited in an autosomal dominant pattern. The mutation was absent in the 200 control individuals and the altered amino acid was completely conserved across species. Functional analysis demonstrated that the GATA6 mutation was associated with a significantly decreased transcriptional activity. The findings provide novel insight into the molecular mechanism involved in the pathogenesis of AF, as well as insight into potential therapies for the prevention and treatment of AF.

A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

“…Similarly, congenital cardiovascular malformations were previously confirmed in AF patients carrying GATA4, GATA5 or GATA6 mutations (49)(50)(51)(52)(53)(54)(55)(56)(57). Markedly, a long list of mutations in these genes has been implicated in a wide variety of congenital cardiovascular anomalies (65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75).…”

“…Developmental biology studies substantiate the key role for several transcription factors, including NKX2.5, GATA4, GATA5 and GATA6, in the normal cardiovascular morphogenesis (46)(47)(48), and multiple mutations in GATA4, GATA5 and GATA6 have been causally associated with AF (49)(50)(51)(52)(53)(54)(55)(56)(57). NKX2.5 is a member of the NK2-family of transcription factors and its expression and functions overlap with those of the GATA family during cardiovascular development, particularly in synergistic regulation of target gene expressions cooperatively with GATA4 (58), which justifies NKX2.5 as a prime candidate gene for AF.…”

Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

“…Atrial fibrillation has been documented in some CHD patients harboring the germline mutations of GATA4, GATA5 and GATA6 (57)(58)(59)(60)(61)(62)(63)(64), which suggests that atrial fibrillation may share a common genetic origin with CHD. However, in the current investigation, no atrial fibrillation was documented in the 2 somatic GATA6 mutation carriers, which may be explained by insufficient electrocardiographic monitoring duration of only 24 h for paroxysmal AF, different genetic background, distinct mutational source, delayed or incomplete penetrance, epigenetic modifiers, or environmental factors (61).…”

Atrial fibrillation: the role of common and rare genetic variants

“…Additional studies have identified novel mutations in GATA6 that co-segregated with AF and resulted in decreased transcriptional activity. 87,88 The LMNA gene encodes lamin A/C, an intermediate filament protein associated with the inner nuclear membrane. Mutations in this gene have been associated with many diseases such as dilated cardiomyopathy and muscular dystrophy.…”