A novel NKX2.6 mutation associated with congenital ventricular septal defect.
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.
Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China, wang_juan1989@sina.cn.
Juan
J
Wang
Jian-Hui
JH
Mao
Ke-Ke
KK
Ding
Wei-Jun
WJ
Xu
Xing-Yuan
XY
Liu
Xing-Biao
XB
Qiu
Ruo-Gu
RG
Li
Xin-Kai
XK
Qu
Ying-Jia
YJ
Xu
Ri-Tai
RT
Huang
Song
S
Xue
Yi-Qing
YQ
Yang
D000293:Adolescent; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006345:Heart Septal Defects, Ventricular / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*
D018398:Homeodomain Proteins; D014157:Transcription Factors; C501915:NKX2-6 protein, human