Mutations in transcription factor NKX2-5, a Drosophila tinman homolog, caused a congenital heart disease associated with mistakes in embryonic cardiac septation. The gene for NKX2-5 is located on chromosome 5q35. Cardiac expression of NKX2-5 continues throughout development and adult life, but its exact function in cardiac abnormalities is unknown. Disruption of a murine homolog of NKX2-5 caused embryonic lethality. Cardiac development was arrested at the linear heart tube stage, prior to looping.
        Cardiac septation is a critical stage in the development of the heart muscle. Without septation, the single atrium and ventricle would not divide into four chambers and normal cardiac function would not occur. Schott et al. tried to identify the genetic defect that causes autosomal dominant atrial septal defect (ASD). The authors followed four families known to have a high incidence of autosomal dominant congenital heart disease. Twenty-seven out of 33 individuals had secundum ASD. They also had other malformations, such as ventricular septal defects, subvalvular aortic stenosis and ventricular hyperplasia. All individuals with congenital heart disease had atrial-ventricular conduction delays. Fourteen had pacemakers. Several of these individuals died.
        Prior to this study, it was already known that NKX2-5 mutations lead to congenital heart defects in lower organisms. The NKX2-5 transcription factor is made up of two exons encoding a 324 amino acid protein. In two families, a C to T transition at NKx2-5 nucleotide 642, which substitutes a methionine codon ATG for threonine codon ACG. In the two other families, mutations caused the expression of truncated NKX2-5 proteins. For example, in one family, a C to T transversion of nucleotide 618 is thought to substitute a termination codon TAG for glutamine CAG codon. Different early embryonic defects are seen in NKX2-5-deficient mice and in normal cardiac structures in heterozygotic mutant mice.
        Identifying downstream targets of NKX2-5 may lead to explanations of the genes responsible for certain congenital heart diseases.

Louiza Patsis, M.S.