A novel PITX2c loss-of-function mutation underlies lone atrial fibrillation

Abstract

Abstract. Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia responsible for substantial morbidity and significantly increased mortality rates. A growing body of evidence documents the important role of genetic defects in the pathogenesis of AF. However, AF is a heterogeneous disease and the genetic determinants for AF in an overwhelming majority of patients remain unknown. In the present study, a cohort of 100 unrelated patients with lone AF and a total of 200 unrelated, ethnically matched healthy individuals used as controls, were recruited. The whole coding exons and splice junctions of the pituitary homeobox 2c (PITX2c) gene, which encodes a paired-like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in the 100 patients and 200 control subjects. The causative potential of the identified mutation of PITX2c was predicted by MutationTaster and PolyPhen-2. The functional characteristics of the PITX2c mutation were assayed using a dual-luciferase reporter assay system. Based on the results, a novel heterozygous PITX2c mutation (p.T97A) was identified in a patient with AF. The missense mutation was absent in the 400 reference chromosomes and was automatically predicted to be disease-causing. Multiple alignments of PITX2c protein sequences across species revealed that the altered amino acid was completely conserved evolutionarily. Functional analysis demonstrated that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild-type counterpart. The findings of the present study firstly link the PITX2c loss-of-function mutation to lone AF, and provide novel insight into the molecular mechanisms underlying AF, suggesting the potential implications for the early prophylaxis and allele-specific therapy of this common type of arrhythmia.

GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy

“…Similarly, mutations in other cardiac transcriptional factor genes, such as GATA4, GATA5, NKX2-5 and PITX2c, were also associated with atrial fibrillation (21)(22)(23)(46)(47)(48)(49)(50)(51)(52)(53). These observations support the hypothesis that a subset of atrial fibrillation may have developmental origin.…”

Novel PITX2c loss-of-function mutations associated with complex congenital heart disease

“…In mice, targeted deletion of PITX2c has been shown to lead to embryonic lethality due to distinct types of CHD, including atrial isomerism, double-outlet right ventricle, atrial septal defect, ventricular septal defect, transposition of the great arteries, and abnormal aortic arch, as well as incomplete closure of the body wall (42). In humans, PITX2c mutations have been implicated in congenital atrial septal defect, ventricular septal defect, double outlet of the right ventricle and atrial fibrillation (51)(52)(53)(54). These findings justify screening PITX2c in other cohorts of patients with CHD.…”

“…Notably, mutant PITX2c has been causally linked to lone or familial atrial fibrillation (53,54). In this study, 2 novel PITX2c mutations were identified in 2families with ventricular septal defect, of which 2 family members also had atrial fibrillation, and 2 family members also had transition of the great arteries.…”

“…The primer pairs used to amplify all the coding exons and exon-intron boundaries of PITX2c by polymerase chain reaction (PCR) were designed as previously described (53). PCR was performed using HotStar Taq DNA Polymerase (Qiagen GmbH, Hilden, Germany) on a Veriti Thermal Cycler (Applied Biosystems, Foster, CA, USA), with standard conditions and concentrations of reagents.…”

Prevalence and Spectrum of PITX2c Mutations Associated with Congenital Heart Disease

“…Yang et al (2013) genotyped PITX2c in 152 unrelated index patients with familial AF and their available relatives, and identified two novel heterozygous PITX2c mutations, p.S37W and p.Y280X, in two families with AF, respectively. Zhou et al (2013) sequenced PITX2c in 100 unrelated patients with lone AF, and found a novel heterozygous PITX2c mutation, p.T97A, in a patient with AF. Functional analysis revealed that the T97A-mutant PITX2c was associated with a significantly decreased transcriptional activity.…”