Molecular genetics of congenital heart disease. A problem of faulty septation.

Abstract

The transition from the single circulation of the embryo to the double circulation of the neonatal and adult heart involves the transformation of the primitive heart tube through a complex morphogenetic process, resulting in completely separated right and left heart chambers and distinct pulmonary and systemic circulations. Septation of heart chambers starts at early stages in embryogenesis and is completed only at birth with the closure of the foramen ovale. Defects in heart septation, including atrial septal defects, atrioventricular canal septal defects, ventricular septal defects, and conotruncal septal defects, represent a major cause of congenital heart disease. The molecular basis of faulty heart septation is now the object of intensive investigation. Mutant genes coding for 2 transcription factors, TBX5 and NKX2.5, have been recently identified by positional cloning in families with high incidence of atrial or ventricular septal defects. Mutations of the TBX5 gene cause the Holt-Oram syndrome, a developmental disorder affecting the heart and the upper limb, the most frequent cardiac abnormalities being atrial and/or ventricular septal defects and conduction defects.1 2 Mutations of the homeobox transcription factor NKX2.5 cause nonsyndromic congenital heart disease, in particular, atrial septal defects and atrioventricular node dysfunction.3 Most mutations so far identified in the TBX5 and NKX2.5 genes induce the formation of truncated proteins resulting in haploinsufficiency. On the other hand, the atrioventricular canal septal defects frequently associated with Down syndrome are probably due to gene overexpression rather than deficiency, namely the presence of 3 copies of chromosome 21 genes. The study of rare patients with partial chromosome 21 trisomy and atrioventricular canal septal defects has allowed the definition of a 2.5-Mb critical region at 21q22.2-q22.3, which is responsible for cardiac malformations: this region should therefore contain one or more genes whose overexpression interferes with correct atrioventricular canal septation.4 Progress …