1. A point mutation in the 5' splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy
- Author
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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., MAURO GIACCA, Pinamonti, B., Sinagra, G., Di Lenarda, A., Silvestri, F., Bussani, R., Davanzo, M., Milasin, J., Muntoni, F., Severini, G. M., Bartoloni, L., Vatta, M., Krajinovic, M., Mateddu, A., Angelini, C., Camerini, F., Falaschi, A., Mestroni, L., Giacca, Mauro, Pinamonti, B., Sinagra, Gianfranco, Di Lenarda, A., Silvestri, Furio, Bussani, Rossana, and Davanzo, M.
- Subjects
Male ,analysis ,Genetic Linkage ,Messenger ,DNA Mutational Analysis ,Cardiomyopathy ,analysis/genetics ,030204 cardiovascular system & hematology ,Dystrophin ,Exon ,0302 clinical medicine ,genetics, Promoter Region ,Dilated ,genetics ,Promoter Regions, Genetic ,genetics, Male, Molecular Sequence Data, Muscle ,Genetics (clinical) ,analysis/genetics, Female, Genetic Linkage, Humans, Intron ,0303 health sciences ,Cardiac muscle ,General Medicine ,Skeletal ,Pedigree ,medicine.anatomical_structure ,Muscle ,Female ,chemistry, Myocardium ,medicine.symptom ,ITGA7 ,Adult ,Cardiomyopathy, Dilated ,medicine.medical_specialty ,X Chromosome ,chemistry, Pedigree, Point Mutation ,genetics, RNA ,RNA Splicing ,Molecular Sequence Data ,genetics/physiopathology ,Biology ,chemistry ,genetics, RNA Splicing ,Promoter Regions ,03 medical and health sciences ,Genetic ,Internal medicine ,Utrophin ,medicine ,analysis, X Chromosome ,Humans ,Point Mutation ,RNA, Messenger ,Myopathy ,Muscle, Skeletal ,Molecular Biology ,030304 developmental biology ,Aged ,Base Sequence ,Myocardium ,genetics/physiopathology, DNA Mutational Analysis, Dystrophin ,Skeletal muscle ,Adult, Aged, Base Sequence, Cardiomyopathy ,analysis/genetics, Female, Genetic Linkage, Humans, Introns ,genetics, Promoter Regions ,medicine.disease ,Molecular biology ,Introns ,Endocrinology ,biology.protein ,RNA - 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.
- Published
- 1996