Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease.

The homeobox transcription factor CSX/NKX2.5, which is a vertebrate homologue of the Drosophila gene tinman, is essential for cardiac development. It is expressed in the early cardiac mesoderm and in heart muscle lineage throughout life. Homozygous deletion of CSX/NKX2.5 causes early embryonic lethality in mice because cardiac development is arrested at the linear heart tube stage. Heterozygous mutation of human CSX/NKX2.5 has been associated with various congenital heart diseases such as atrial septal defect (ASD), ventricular septal defect, tetralogy of Fallot, and tricuspid valve abnormalities, including Ebstein's anomaly. Additionally, CSX/NKX2.5 mutation causes atrioventricular (AV) conduction block with or without associated congenital heart diseases. Ten different heterozygous mutations have been already reported and a new point mutation, which is a C-to-A transition (Cys264ter) at nucleotide 901 of CSX/NKX2.5, results in the production of a truncated protein occurring COOH-terminal to the homeodomain of CSX/NKX2.5. The mutation was found in a patient with familial ASD and first-degree AV block; 4 members from 3 generations had secundum-type ASD and first-degree AV block.