X-linked dilated cardiomyopathy (XLDC) is a familial
heart disease presenting in young males as a rapidly progressive
congestive heart failure, without clinical signs of skeletal
myopathy. This condition has recently been linked to the
dystrophin gene in some families and deletions encompassing the genomic region coding for the first muscle exon have been detected. In order to identify the defect responsible for this disease at the molecular level and to understand the reasons for the selective heart involvement, a family with a severe form of XLDC was studied. In the affected members, no deletions of the
dystrophin gene were observed. Analysis of the muscle promoter, first exon and intron regions revealed the presence of a single point mutation at the first exon-intron boundary, inactivating the universally conserved
5' splice site consensus sequence of the first intron. This mutation introduced a new restriction site for MseI, which cosegregates with the disease in the analyzed family. Expression of the major
dystrophin mRNA isoforms (from the muscle-, brain- and Purkinje cell-promoters) was completely abolished in the myocardium, while the brain- and Purkinje cell- (but not the muscle-)
isoforms were detectable in the skeletal muscle. Immunocytochemical studies with anti-
dystrophin antibodies showed that the
protein was reduced in quantity but normally distributed in the skeletal muscle, while it was undetectable in the cardiac muscle. These findings indicate that expression of the muscle
dystrophin isoform is critical for myocardial function and suggest that selective heart involvement in
dystrophin-linked
dilated cardiomyopathy is related to the absence, in the heart, of a compensatory expression of
dystrophin from alternative promoters.