Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease

Abstract

Heterozygous mutations in the human transcription factor gene NKX2.5 are associated with either isolated or combined congenital heart disease (CHD), primarily secundum atrial septal defect-II (ASD-II), ventricular septal defect (VSD) or tetralogy of Fallot (TOF). Thus, NKX2.5 has an important role at different stages of cardiac development. The frequency of NKX2.5 mutations in a broader phenotypic spectrum of CHD is not completely determined. Here, we report the identification of two novel mutations in the NKX2.5 gene in a screening of 121 patients with a broad spectrum of CHDs. However, mutations were only associated with familial ASD-II and in both, patients also showed atrioventricular (AV) block. We found one missense mutation (R190L) in two siblings with ASD-II and a frame-shift mutation (A255fsX38) at the C-terminus in a mother and daughter. In addition, a single patient with hypoplastic left heart syndrome (HLHS) had the reported sequence variant R25C. Importantly, sporadic cases of CHD that share phenotypic aspects of NKX2.5 mutation carriers were negative for genetic analysis. Thus, even important for cardiac development, germline mutations in NKX2.5 are rare in patients with sporadic CHD and genetic and/or pathophysiologic heterogeneity is likely for sporadic forms of CHD.

Novel NKX2-5 mutations responsible for congenital heart disease

“…To date, more than 40 mutations in NKX2-5 have been described, of which more than 30 mutations have been observed in patients with atrial septal defect, showing that although NKX2-5 mutations are involved in a long list of cardiac malformations, the most frequent phenotype resulted is atrial septal defect (Stallmeyer et al, 2010). In most of these patients, the CHD-causing mutations are familial, whereas sporadic cases remain relatively infrequent (Elliott et al, 20003;Sarkozy et al, 2005).…”

“…Also, mutations in cardiac structural proteins as alpha myosin heavy chain (MYH6) and alpha cardiac actin (ACTC1) were identified in familial CHD (Ching et al, 2005;Matsson et al, 2008). However, so far, only NKX2-5 mutations were reported to cause an atrial septal defect phenotype and development of atrioventricular block (Stallmeyer et al, 2010). The two most common phenotypes caused by mutated NKX2-5 are atrial septal defect and atrioventricular conduction disturbance (Akazawa and Komuro, 2005), indicating the crucial role of NKX2-5 not only in the morphogenesis of the heart, but also in the construction of cardiac conduction system.…”

“…We also carried out a physical examination, ECG, and echocardiography, and all individuals were screened for the identified mutations in NKX2-5 by direct sequencing. A total of 200 unrelated, ethnically matched healthy individuals, who were enrolled from the general population and had no evidence for any type of CHD following the comprehensive evaluation of their individual and familial histories, detailed review of the medical records, and complete physical examination (Stallmeyer et al, 2010), were used as controls to screen for the identified mutations. Peripheral venous blood samples were collected from subjects and control individuals.…”

“…Due to its crucial role in normal cardiogenesis, NKX2-5 has been a prime candidate gene in studies to identify the genetic determinants for congenital structural heart defects. To date, more than 40 mutations within the NKX2-5 gene have been identified in patients with a variety of congenital heart malformations, including atrial septal defect with normal or abnormal atrioventricular conduction, ventricular septal defect, conotruncal abnormalities as tetralogy of Fallot, double-outlet right ventricle, L-transposition of the great arteries, and hypoplastic left heart syndrome (Stallmeyer et al, 2010). These observations strongly suggest that NKX2-5 is important in the later stages of heart development and maturation, in addition to its role in cardiac progenitor commitment and patterning in the developing heart (Prall et al, 2007).…”

Epidemiology and Etiology of Congenital Heart Diseases

“…Mutations in NKX2-5 result in loss of heart formation in the embryo and have been found in sporadic www.intechopen.com CCVM. Although the contributions of these variants to the disease phenotype remains uncertain, the linkage between this gene disorder and the atrioventricular conduction defect, ASD, VSD or TOF, have been found (Elliott et al, 2003;McElhinney et al, 2003;Stallmeyer et al, 2010).  TBX1, T-box 1 transcription factor, the T-box family; The human TBX1 gene encodes another T-box transcription factor, expressed in neural crest and the developing cardiac outflow tract (conotruncus) (Calmont et al, 2009).…”