CONGENITAL HEART-DISEASE CAUSED BY MUTATIONS IN THE TRANSCRIPTION FACTOR NKX2-5

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 atrio ventricular conduction abnormalities was mapped to chromosome 5q35, wh ere NKX2-5, a Drosophila tinman homolog, is located. Three different N KX2-5 mutations were identified. Two are predicted to impair binding o f NKX2-5 to target DNA, resulting in haploinsufficiency, and a third p otentially augments target-DNA binding. These data indicate that NKX2- 5 is important for regulation of septation during cardiac morphogenesi s and for maturation and maintenance of atrioventricular node function throughout life.