A point mutation in the 5' splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy

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