NKX2-5: an update on this hypermutable homeodomain protein and its role in human congenital heart disease (CHD)

Abstract

Congenital heart disease (CHD) is among the most prevalent and fatal of all birth defects. Deciphering its causes, however, is complicated, as many patients affected by CHD have no family history of the disease. There is also widespread heterogeneity of cardiac malformations within affected individuals. Nonetheless, there have been tremendous efforts toward a better understanding of the molecular and cellular events leading to CHD. Notably, certain cardiac-specific transcription factors have been implicated in mammalian heart development and disruption of their activity has been demonstrated in CHD. The homeodomain transcription factor NKX2-5 is an important member of this group. Indeed, more than 40 heterozygous NKX2-5 germline mutations have been observed in individuals with CHD, and these are spread along the coding region, with many shown to impact protein function. Thus, NKX2-5 appears to be hypermutable, yet the overall detection frequency in sporadic CHD is about 2% and NKX2-5 mutations are one-time detections with single-positives or private to families. Furthermore, there is lack of genotype-phenotype correlation, in which the same cardiac malformations have been exhibited in different NKX2-5 mutations or the same NKX2-5 mutation associated with diverse malformations. Here, we summarize published NKX2-5 germline mutations and explore different avenues in disease pathogenesis to support the notion of a multifactorial cause of CHD where possibly several genes and associated pathways are involved.

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

“…47) In humans, an increasing number of NKX2-5 mutations have been associated with various congenital heart diseases including ASD, ventricular septal defect, Fallot's tetralogy, hypoplastic left ventricle transposition of the great arteries and valvular deformities, cardiac arrhythmias including cardiac conduction block and atrial fibrillation, and DCM. 32,33,52) Collectively, these findings along with the present study indicate that NKX2-5 plays important roles not only in early cardiovascular morphogenesis, but also in the postnatal maturation and homeostasis of cardiomyocytes and the adaptive remodeling of adult heart. Notably, NKX2-5 physically interacts with such cooperative partners as GATA4, TBX5, and TBX20, and has been shown to cooperatively regulate the transcription of several essential cardiac target genes, such as troponin I, troponin C, α-actin, and α-myosin heavy chain, 37) and furthermore, mutations in these cooperative partners and cardiac target genes have been causally related to DCM.…”

Nkx2-5 Mutations in Patients With Nonsyndromic Congenital Heart Disease

“…These mutations are single nucleotide substitutions, deletions and insertions. The Nkx2-5 mutations are spread along the gene, and except for one at a splice site, all are located in the coding region [25].…”

“…Draus et al argue that the reason for occurring several missense mutations in one patient could be the use of formalin for sample fixation and also the long period of fixation [26]. Reamon-Buettner and Borlak conduct a similar study on fresh tissue and report that germ line mutation is the cause of disease [25].…”

Fbxo25 controls Tbx5 and Nkx2–5 transcriptional activity to regulate cardiomyocyte development

“…Thus, Nkx2-5 null mice exhibit an abnormal cardiac looping phenotype [24], indicating that Nkx2-5 is essential for cardiac development. Therefore, Nkx2-5 is a cardiac specific transcription factor to regulate cardiac development and heart diseases [25].…”