| Project/Area Number |
13470138
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 INSTITUTE OF NEUROSCIENE, NATIONAL CENTER OF NEUROLOGY AND PSYCHIATRY (NCNP) |
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Principal Investigator |
NISHINO Ichizo NATIONAL INSTITUTE OF NEUROSCIENE, NATIONAL CENTER OF NEUROLOGY AND PSYCHIATRY (NCNP), DIRECTOR, 疾病研究第一部, 部長 (00332388)
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| Co-Investigator(Kenkyū-buntansha) |
MURAKAMI Nobuyuki DOKKYO UNIVERSITY, SCHOOL OF MEDICINE, 越谷病院・小児科, 講師 (00316598)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥12,200,000 (Direct Cost: ¥12,200,000)
Fiscal Year 2003: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥5,200,000 (Direct Cost: ¥5,200,000)
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| Keywords | lysosome / myopathy / autophagic vacuole / Danon disease / rimmed vacuoles / distal myopathy / 自己貧食空胞 / 自己貪食空砲 / 縁取り空砲 |
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| Research Abstract |
We clinicopathologically characterized 38 patients from 13 distinct families with genetically confirmed Danon disease. Cardiomyopathy and myopathy were seen in all men but mental retardation was present in 70% of men. Serum CK level is elevated in all men but only in 63% of women. Men died at age 19±6 years while women died at age 40±7 years, both due to cardiac failure. All women developed lethal cardiomyopathy even though they had milder symptoms. We identified two new forms of autophagic vacuolar myopathy (AVM) which resembles Danon disease but are genetically distinct : adult-onset AVM with multi-organ involvement and X-linked AVM resembling congenital myopathy. The latter disease was mapped to Xq28. LC3,which is supposed to be degraded immediately after the fusion between autophagosomes and lysosomes, was not degraded in the X-linked AVM, suggesting an abnormality in the degradation process.
We identified that the GNE gene encoding UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK) is the causative gene for distal myopathy with rimmed vacuoles (DMRV) just as in hereditary inclusion body myopathy. Recombinant proteins with mutations found in patients showed that those with mutations in GNE domain had decreased GNE activity while those with MNK mutations had decreased MNK activity.
Sialylation was decreased in patients' cells, which was recovered by adding ManNAc or NeuAc. Our results suggest a possibility of curative therapy for DMRV.
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