| Budget Amount *help |
¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1996: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1995: ¥4,900,000 (Direct Cost: ¥4,900,000)
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| Research Abstract |
An increasing number of current knowledge of clinical, biological and molecular genetic changes of progressive muscular dystrophy (PMD) have obtained. Our research progress through this project provided a new insights into the understanding of PMD which is considered to be a group of heterogenous disorders. Future studies must be focused towards the isolation of genes and molecular analysis of the gene products in these diverse muscular dystrophies, as well as functional analysis of proteins related with PMD.
Research projects accomplished were, (1) Emery-Dreifuss muscular dystrophy (EDMD), (2) Congenital muscular dystrophy (CMD), (3) Facioscapulohumeral muscular dystrophy (FSHD), and (4) Miyoshi distal muscular dystrophy (MDMD). In EDMD,we identified novel nonsense mutations of the STA gene in patients with EDMD.The human STA gene mapped in the teromeric region of Xq28 has an open reading frame of 762 nucleotides which encodes a protein of 254 amino acids named 'emerin'. We have identi
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fied cellular localization of the STA gene product (emerin) to the nuclear membrane. CMD refers to a heterogeneous group of genetic disorders characterized by severe dystrophic muscle wasting from birth or early infancy. By light microscopy we previously obtained immunocytochemical evidence for basal lamina (BL) abnormality of skeletal muscle in Fukuyama congenital muscular dystrophy (FCMD). To further elucidate the pathological involvement of the BL in FCMD,we examined by electron microscopy the skeletal muscle in 12 cases of FCMD,9 cases of age-matched neuromuscular diseases unrelated to FCMD,and a case of merosin-negative CMD (MCMD). We found that the BL of skeletal muscle fibers in all patients with FCMD and the MCMD patient had a thin, deranged and often disrupted appearance. Our results indicate the presence of fragile BL which may precede plasma membrane damage in FCMD skeletal muscle. In FSHD,we have examined 92 Japanese families with possible FSHD.Among these 77 families were confirmed to have 4q35-teromeric rearrangements associated with the disease. Eleven severely affected patients (unrelated) had EcoRl fragment smaller than 11kb. Restriction enzyme maps of the genomic fragments in the two patients revealed that the 10 kb fragments were identical and contained only one 3.3kb Kpnl repeat unit. Sequence analysis across the deletion break points showed that the 5' and the 3' elements have the same sequence, and thus suggested the presence of recombination events. We established somatic cell colones from several FSHD patients, which can be provided for detailed chromosome analysis in the teromeric region. In collaboration with Dr. Robert H.Brown, Jr., we mapped the Miyoshi gene to chromosome 2p12-14. The polymorphic microsatellite markers around the locus will provide extremely useful diagnostic information regarding the disease. Less
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