1997 Fiscal Year Final Research Report Summary
Study on pathogenasis of the heteroplasmic mutation of mitochondrial DNA in mitochondrial disease
| Project/Area Number |
08670849
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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 |
Pediatrics
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| Research Institution | Tohoku University |
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Principal Investigator |
MIYABAYASHI Shigeaki Department of Pediatrics, Tohoku University School of Medicine, Associate Professor, 医学部, 助教授 (20174203)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Atsushi Department of Pediatrics, Tohoku University School of Medicine, Research Associa, 医学部・附属病院, 助手 (20292336)
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| Project Period (FY) |
1996 – 1997
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| Keywords | mitochondrial DNA / heteroplasmy / mutation / MELAS / Leigh's disease / segregation / tissue-specific |
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| Research Abstract |
An increasing number of maternally inherited diseases has been shown to be associated with point mutations of mtDNA.The pathogenesis of this disorder is characterized by a heteroplasmic mtDNA consisted with wild-type and mutant. A point mutation lies in the region of tRNAs of mtDNA like as tRNALeu (UUR) (A3243G) or tRNALys (A8344G). The other point mutation is found at the protein-coding region like as ATPase 6 (T8993G/C) or subunits 4 and 1 of NADH dehydrogenase (G11778A,G3460A). We studied quantitative analysis of mutation in various autopsied tissues from a MELAS patient or a MERRF patient. The A3243G mutation of MELAS was present in different population of mutation in different tissues from the same patient. There were especially low amounts in usually dividing cells like as skin, blood, born marrow cell and spleen. On the other hand, T8993G mutation of Leigh syndrome was present in similar amounts in all tissues. A3243G mutation showed tissue-specific heteroplasmy, but T8993G mutation did not. The analysis of heteroplasmy investigated using cultured fibroblasts. The population of A3243G mutation is unstable during many times spriting culture, but T8993G mutation is stable. The quantitative analysis by single cell PCR found that the population of A3243G mutation was different and heterogeneous in each cell, the other hand, that of T8993G mutation was almost same and homogenous. There may be a rapid segregation of T8993G mutation in oocytes. Differences in clinical manifestation may be mainly due to tissue-specific heteroplasmy in the former, but due to different tissue-specific thresholds in the latter.
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[Publications] Suzuki, S., Y.Hinokio, S.Hirai, M.Onoda, M.Matsumoto, M.Ohtomo, H.Kawasaki, Y.Satoh, H.Akai, K.Abe, S.Miyabayashi.E.Kawasaki, S.Nagataki and T.Toyota: "Pancreatic beta-cell secretort defect associated with mitochondrial point mutation of the tRNALEU (UUR) gene : a study in seven families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)." Deabetrologia. 37. 818-825 (1994)
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[Publications] Hayashi, J-I., S.Ohta., Y.Kagawa, D.Takai, H., S.Miyabayashi, K.Tada, H.Fukushima, K.Inui, S.Okada, Y-i.Goto and I.Nonaka.: "Functional and morphological abnormalities of mitochondria in human cells containing mitochondrial DNA with pathogenic point mutations in tRNA genes." J.Biol.Chem.269. 19060-19066 (1994)
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