A Novel NKX2.6 Mutation Associated with Congenital Ventricular Septal Defect

Abstract

Congenital heart disease (CHD) is the most common birth defect and is the most prevalent non-infectious cause of infant death. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous and the genetic determinants for CHD in an overwhelming majority of patients remain unknown. In this study, the coding regions and splice junctions of the NKX2.6 gene, which encodes a homeodomain transcription factor crucial for cardiovascular development, were sequenced in 210 unrelated CHD patients. As a result, a novel heterozygous NKX2.6 mutation, p.K152Q, was identified in an index patient with ventricular septal defect (VSD). Genetic analysis of the proband's available family members showed that the mutation cosegregated with VSD transmitted as an autosomal dominant trait with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across species. Due to unknown transcriptional targets of NKX2.6, the functional characteristics of the identified mutation at transcriptional activity were analyzed by using NKX2.5 as a surrogate. Alignment between human NKX2.6 and NKX2.5 proteins displayed that K152Q-mutant NKX2.6 was equivalent to K158Q-mutant NKX2.5, and introduction of K158Q into NKX2.5 significantly reduced its transcriptional activating function when compared with its wild-type counterpart. This study firstly links NKX2.6 loss-of-function mutation with increased susceptibility to isolated VSD, providing novel insight into the molecular mechanism underpinning VSD and contributing to the development of new preventive and therapeutic strategies for this common form of CHD.

Identification of candidate genes for congenital heart defects on proximal chromosome 8p

“…Missense or frameshift mutations in NKX2-6 have been found in different CHDs including persistent truncus arteriosus/common arterial trunk1922, TFO, DORV, and VSD2324. However, the functional role of NKX2-6 is far from clarified because there have been no detailed functional studies of NKX2-6 mutations.…”

Cardiac Development: A Glimpse on Its Translational Contributions

“…Over the last decade our understanding of the genetic culprits underlying cardiac septation has enormously increased. Mutations in NKX2.5 and GATA4, have been associated to atrial septal defects [404][405][406][407][408][409] while mutations HAND2, NKX2.5, and NKX2.6 have been associated to ventricular septal defects [411][412][413]. Similarly, other genes have been associated to controtuncal defects [414][415][416], including DORV [417] as well as to complex congenital cardiopathies such as Tetralogy of Fallot [418,419] (Figure 3C).…”

Hematological and demographic profile of Pakistani children with isolated ventricular septal defects (VSDs)

“…Cardiac morphogenesis is a complex process that requires a complex interaction of different factors, including the differentiation, proliferation, migration, commitment to perform normal physiology, programmed cell death, and coordination of cardiac cells. Genetic risk factors and environment can disrupt the normal physiology of cardiogenesis that may lead to a broad spectrum of heart anomalies [1]. Contemporary classification of cardiovascular abnormalities varies based on clinically specified anatomic lesions.…”