Congenital Heart Disease Caused by Mutations in the Transcription Factor <i>NKX2-5</i>

TLDR

A dominant locus for cardiac malformations and conduction defects maps to chromosome 5q35, where the NKX2‑5 transcription factor resides. Mutations in NKX2‑5, including three identified variants that either impair or enhance DNA binding, cause nonsyndromic congenital heart disease by disrupting septation and atrioventricular node development and function.

Abstract

Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease. A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5 , a Drosophila tinman homolog, is located. Three different NKX2-5 mutations were identified. Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding. These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life.