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

Jelena Milasin, Francesco Muntoni, Giovanni Maria Severini, Lucia Bartoloni, Matteo Vatta, Maja Krajinovic, Anna Mateddu, Corrado Angelini, Fulvio Camerini, Arturo Falaschi, Luisa Mestroni, Mauro Giacca, Bruno Pinamonti, Gianfranco Sinagra, Andrea Di Lenarda, Furio Silvestri, Rossana Bussani, Milla Davanzo

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Abstract

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 Msel, 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.

Original languageEnglish
Pages (from-to)73-79
Number of pages7
JournalHuman Molecular Genetics
Volume5
Issue number1
Publication statusPublished - Jan 1996

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ASJC Scopus subject areas

  • Genetics

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Milasin, J., Muntoni, F., Severini, G. M., Bartoloni, L., Vatta, M., Krajinovic, M., Mateddu, A., Angelini, C., Camerini, F., Falaschi, A., Mestroni, L., Giacca, M., Pinamonti, B., Sinagra, G., Di Lenarda, A., Silvestri, F., Bussani, R., & Davanzo, M. (1996). A point mutation in the 5′ splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy. Human Molecular Genetics, 5(1), 73-79.