Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect

Abstract

Recently, GATA4 and NKX2.5 were reported as the disease genes of atrial septal defect (ASD) but the relationship between the locations of their mutations and phenotypes is not clear. We analyzed GATA4 and NKX2.5 mutations in 16 familial ASD cases, including four probands with atrioventricular conduction disturbance (AV block) and two with pulmonary stenosis (PS), by PCR and direct sequencing, and examined their phenotypes clinically. Five mutations, including two GATA4 and three NKX2.5 mutations, were identified in 31.3% of the probands with ASD, and three of them were novel. The two GATA4 mutations in the probands without AV block were S52F and E359Xfs (c.1075delG) that was reported previously, and three NKX2.5 mutations in the probands with AV block were A88Xfs (c.262delG), R190C, and T178M. Additionally, we observed some remarkable phenotypes, i.e., dextrocardia with E359Xfs (c.1075delG) and cribriform type ASD with R190C, both of which are expected to be clues for further investigations. Furthermore, progressive, most severe AV block was closely related with a missense mutation in a homeodomain or with a nonsense/frame-shift mutation of NKX2.5 for which classification has not been clearly proposed. This pinpoints essential sites of NKX2.5 in the development of the conduction system.

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

“…27 Mutations in GATA4 TAD regions have been related to septal defects in different studies. 10,17 This study found that the identified mutation in GATA6 TAD region was also associated with ASDs, further supporting the point of a redundant role between GATA4 and GATA6 in cardiogenesis as mentioned earlier. 7,20,21,27,28 A disrupted interaction between GATA4 and TBX5 is involved in ASDs in both humans and mice.…”

“…9 Numerous mutations in GATA4 have been recognized in a wide range of cases, including tetralogy of Fallot (TOF), pulmonary stenosis, atrial septal defects (ASDs), ventricular septal defects, atrioventricular septal defects and patent ductus arteriosus. 4,[10][11][12][13][14][15][16][17] GATA6 is another member of the GATA family with expression and functions that overlap with GATA4 during cardiovascular development. 7 Recent experiments in animals have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, highlighting the potential involvement of GATA6 mutations in the pathogenesis of human CHD.…”

GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

“…Screening for mutations of SEMA3C and PLXNA2 may provide further evidence of the involvement of semaphorin-plexin signaling in human OFT defects. It is of note that GATA6 mutations identified in humans were associated with PTA, in contrast with GATA4 mutations, which are commonly associated with atrial and/or ventricular septal defects (20)(21)(22). This result suggests that GATA6 may play a dominant role in OFT development, although Gata6 has been reported to have a redundant role with Gata4 during cardiogenesis (25,(34)(35)(36).…”

“…Establishment of genomic bank with cell lines, extraction of genomic DNA samples were reported previously (21,41). All exons and flanking introns of GATA6 were PCR amplified and sequenced using direct, bidirectional sequencing; a detailed procedure is given in SI Materials and Methods.…”

“…Null mutation of Gata4 in mice results in embryonic lethality because of defects in cardiogenesis (18,19). Mutations of GATA4 in humans were identified to cause CHD characteristic of atrial and/or ventricular septal defects (20,21), and heterozygous mutations of Gata4 in mice recapitulate the human phenotype (22). Systemic ablation of Gata6 in mice also results in embryonic lethality (23), whereas conditional inactivation of Gata6 in the CNC results in perinatal mortality from OFT defects, typically PTA (24).…”