Association of nonsense mutation of dystrophin gene with disruption of sarcoglycan complex in X-linked dilated cardiomyopathy

Background In a systematic analysis of inherited forms of cardiomyopathy, w e previously identified a family with X-linked dilated cardiomyopathy chara cterised by a mutation in the rod region of dystrophin. We have now attempt ed to eludicate the genetic mechanism involved in this disease, as well as the role of dystrophin-associated glycoproteins. Methods The affected dystrophin epitope, which lacks binding to the dys-1 a ntibody, was analysed by single-strand conformation polymorphism analysis, reverse-transcription PCR, and DNA sequencing. Effects on dystrophin-associ ated glycoproteins were studied by immunohistochemistry and western blottin g. Findings A translation-termination mutation (C4148T) in exon 29 of the dyst rophin gene was found in all affected family members. Alternative splicing rescued the reading frame and led to the expression of a dystrophin molecul e lacking 50 aminoacids both in cardiac and skeletal muscle. Immunohistoche mical analysis of the dystrophin-associated proteins revealed a reduction o f beta-sarcoglycan and delta-sarcoglycan in the sarcolemma of cardiac muscl e but not skeletal muscle tissue. However, western blotting revealed simila r amounts of sarcoglycan subunits in both tissues. Interpretation The molecular mechanism of this subtype of X-linked cardiomy opathy may be explained by a conformational change in exon-29-deleted dystr ophin, resulting in disruption of the sarcoglycan assembly in heart muscle but not skeletal muscle.