Genetic analysis of an enhancer of the NKX2-5 gene in ventricular septal defects

• Published in: Gene 2012-10, Vol.508 (1), p.106-109
• Main Authors: Qin, Xianyun, Xing, Qining, Ma, Liming, Meng, Haihong, Liu, Yumei, Pang, Shuchao, Yan, Bo
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Base Sequence; cardiomyocytes; Case-Control Studies; Child; Child, Preschool; congenital abnormalities; Congenital heart disease; embryogenesis; Enhancer; enhancer elements; Enhancer Elements, Genetic - genetics; etiology; Female; genetic techniques and protocols; Genetic Variation - genetics; heart; heart diseases; Heart Septal Defects, Ventricular - genetics; Homeobox Protein Nkx-2.5; Homeodomain Proteins - genetics; homeotic genes; Humans; Infant; Infant, Newborn; Male; Molecular Sequence Data; morphogenesis; mutation; NKX2-5; patients; Promoter Regions, Genetic - genetics; Sequence variants; transcription factors; Transcription Factors - genetics; Ventricular septal defects; Young Adult
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2012.07.019

Congenital heart disease (CHD) is one of the most common birth defects in humans. Mutations in cardiac transcription factor genes, such as GATA4, NKX2-5 and TBX5 genes, have been associated to a small portion of familial and isolated CHD cases. NKX2-5, a highly conserved homeobox gene, is expressed in the developing heart. During embryonic development, NKX2-5 plays pivotal roles in specifying cardiac progenitors, cardiac morphogenesis, cardiomyocyte differentiation and conduction system development. Numerous mutations in NKX2-5 gene have been reported in CHD patients, including atrial septal defect, ventricular septal defect (VSD) and tetrology of Fallot. We have previously identified the sequence variants within the NKX2-5 gene promoter in VSD patients. As several studies have revealed that the NKX2-5 gene is regulated by a complex module involving promoter and multiple independent cardiac enhancers, one of which is located between −3500bp and −2500bp upstream to the transcription start site, we hypothesized that the variants within the cardiac enhancer may contribute to CHD. In this study, we genetically analyzed the enhancer of NKX2-5 gene in large cohorts of VSD patients (n=322) and controls (n=336). The results showed that three novel variants, g.1467G>A, g.1487Ins with a 13bp insertion and g.1515Ins with a 6bp insertion, were identified within the enhancer element in both VSD patients and controls with similar frequencies (P>0.05). Therefore, our data suggested that the enhancer of NKX2-5 gene may not be a contributor to the VSD etiology. Other regulatory elements of the NKX2-5 gene will be further analyzed in CHD patients. ► We genetically analyzed an enhancer of NKX2-5 gene in a large cohort of VSD patients. ► Three novel variants were identified in VSD patients and controls with similar frequencies. ► The variants within the NKX2-5 gene enhancer did not a contribute to the VSD etiology. ► The other regulatory elements of NKX2-5 gene will be examined in CHD patients.