2007 Fiscal Year Final Research Report Summary
Clarification of pathomechanism of inherited muscular disorder due to abnormality of sarcomeric proteins
| Project/Area Number |
18590964
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | National Center of Neurology and Psychiatry |
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Principal Investigator |
MINAMI Narihiro National Center of Neurology and Psychiatry, National Institute of Neuroscience, Depertment of Neuromuscular Research, Adjunct Researcher (20392417)
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| Co-Investigator(Kenkyū-buntansha) |
NISHINO Ichizo National Institute of Neuroscience, Depertment of Neuromuscular Research, Director (00332388)
HAYASHI Yukiko National Institute of Neuroscience, Depertment of Neuromuscular Research, Section chief (50238135)
NOGUCHI Satoru National Institute of Neuroscience, Depertment of Neuromuscular Research, Section chief (00370982)
NONAKA Ikuya National Institute of Neuroscience, Honorary member (80040210)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Neuromuscular disorders / sarcomere / calpain 3 / cDNA microarray / myofibrillar myopathy / myotilin / ZASP / limb-girdle muscular dystrophy |
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| Research Abstract |
1. cDNA microarray analysis of calpainopathy Muscles from calpainopathy patients show focal necrosis and regeneration at earlier stage, but lobukted fiber formation at later chronic stage. We compared the gene expression profiles of these two stages with control muscles using a cDNA microarray customized for skeletal muscle specific genes. We identified 29 genes whose mRNA expression were specifically altered in muscles with lobulated fibers, especially the genes of actin regulatory proteins, including gelsolin, PDLIM3 and troponin I1. We proposed that abnormal gene expression for actin regulatory proteins may contribute to alter myofibril organization, showing lobulated fibers.
2. Mutation analysis and characterization of myofibrillar myopathy(MFM) MFM is a group of disorders based on histopathological features, showing myofibrillar disorganization with protein aggregates. This is the first large-scale of genetic study of MFM in Japan. (1) We selected 47 patients whose muscle pathology is consistent with MFM. We found one patient with desmin gene mutation, but no patient had mutations in αB-crystallin, ZASP and myotilin genes, This result suggests that most of the Japanese MFM patients may have mutations in the gene(s) still yet unidentified. (2) ZASP mutations can show various clinical features. Thus, we examined ZASP mutation in 200 patients showing disorganization of intermyofibrillar networks as a major pathological feature. One patient with high CKemia and three patients who were clinically diagnosed to have sIBM had mutations in ZASP. Interestingly, multi-minicores were the most striking pathological finding in the skeletal muscle from one of the patients. This is the first report that zaspopathy can cause multi-minicores. (3) We also found the first Japanese limb-girdle muscular dystrophy type 1A due to myotilin gene mutation. (4) We chose cofilin 2 as a candidate gene for MFM, but no mutation was found in 80 patients.
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