Sporadic cases of dilated cardiomyopathies associated with atrioventricular conduction defects are not linked to mutation within the connexins 40 and 43 genes.

Dilated cardiomyopathies are common forms of primary myocardial disorders responsible for severe heart failure which may require cardiac transplantation. Viral infection, alcohol, carnitine deficiency or mutation within the dystrophin gene have been recognized as causative for the myopathy. Epidemiological studies have shown that approximately 20% of these cardiomyopathies are inherited. A subset of dilated cardiomyopathies are associated with severe atrioventricular conduction defects. This clinical entity is rare and mitochondrial mutations can cause the disease but usually affect other organs besides the myocardium. A large kindred with autosomal dominant transmission of dilated cardiomyopathy associated with atrioventricular conduction defects was carefully studied a few years ago. A genome-wide linkage analysis with this pedigree identified a disease locus mapped to chromosome 1p11q1. Several candidate genes are mapped to this region, including the gap junction protein connexin 40 gene. Moreover, the selective disruption of the murine connexin 40 (Cx40) was shown to be responsible for atrioventricular block, supporting the hypothesis that this gene could be a candidate gene to human heart conduction abnormalities. Connexin 43 (Cx43) is the predominant junction protein in the heart and it is thought to modulate the contractibility and the electrical coupling of cardiac myocytes. In human hypertrophic and ischaemic hearts, Cx43 content in the myocardium was shown to be reduced. Based on these functional data observed in humans and animals together with the genetic epidemiological data, we investigated whether mutation within the coding region of the Cx40 and Cx43