Assessment of the CTNNA3 gene encoding human αT-catenin regarding its involvement in dilated cardiomyopathy

alphaT-catenin is a novel member of the alpha-catenin family, which shows most abundant expression in cardiomyocytes and in peritubular myoid cells of the testis, pointing to a specific function for alphaT-catenin in particular muscle tissues. Like other alpha-catenins, alpha-catenin provides an indispensable link between the cadherin-based cell-cell adhesion complex and the cytoskeleton, to mediate cell-cell adhesion. By isolating genomic clones, combined with database sequence analysis, we have been able to determine the structure of the CTNNA3 and Ctnna3 genes, encoding human and mouse alphaT-catenin, respectively. The positions of the exon-exon boundaries are completely conserved in CTNNA3, Ctnna3, and the alphaN-catenin encoding CTNNA2 gene. They overlap largely with the boundaries of the CTNNA1 and CTNNAL1 genes encoding alphaE-catenin and alpha-catulin, respectively. This emphasizes that these alpha-catenin genes evolved from the same ancestor gene. Nevertheless, the introns of CTNNA3 and Ctnna3 are remarkably large (often more than 100 kb) compared with introns of other CTNNA genes. The CTNNA3 gene was mapped to chromosome band 10q21 by both fluorescence in situ hybridization and polymerase-chain-reaction-based hybrid mapping. This region encodes a gene for autosomal dominant familial dilated cardiomyopathy (DCM), a common cause of morbidity and mortality. As alphaT-catenin is highly expressed in healthy heart tissue, we have considered CTNNA3 as a candidate disease gene in a family showing DCM linkage to the 10q21-q23 locus. Mutation screening of all 18 exons of the CTNNA3 gene in this family has, however, not detected any DCM-linked CTNNA3 mutations.