HUMAN DESMIN GENE - CDNA SEQUENCE, REGIONAL LOCALIZATION AND EXCLUSION OF THE LOCUS IN A FAMILIAL DESMIN-RELATED MYOPATHY

Desmin is a muscle-specific intermediate filament that is encoded by a gene assigned to human chromosome 2q35. Desmin-related myopathies are inherited disorders characterized by an intrasarcoplasmic accumulatio n of desmin, Recently, the knockout of the desmin gene was shown to ge nerate a myopathic syndrome in transgenic mice, suggesting that functi onal abnormality of desmin may generate similar clinical symptoms in m ouse and human. To determine the potential role of the desmin gene in a well-defined desmin-related myopathy (autosomal dominant form of Far deau), human desmin cDNAs obtained from affected and unaffected indivi duals were cloned, sequenced and compared, No obvious mutation was det ected. A BssHII restriction fragment length polymorphism (RFLP) was id entified in exon 6 of the desmin gene. This RFLP was associated with a previously identified EcoRV RFLP in exon 4 to generate a tetra-alleli c system, which was tested for linkage to the desmin-related myopathy in three families, The human desmin gene was localized within an 11-cM interval on chromosome 2q using a panel of radiation hybrids. This 11 -cM region was clearly excluded by linkage analysis in the three desmi n-related myopathy families using a set of highly polymorphic microsat ellite markers. These results suggest that the desmin gene is not prim arily involved in this disease.