2019 Fiscal Year Final Research Report
Elucidation of the causes of undiagnosed mitochondrial disease by quantitative and qualitative evaluation of respiratory chain complexes
| Project/Area Number |
16K09999
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Teikyo University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Keywords | ミトコンドリア病 / ミトコンドリア呼吸鎖複合体 / 遺伝子診断 / 生化学診断 |
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| Outline of Final Research Achievements |
To identify the causes of suspected but undiagnosed mitochondrial disorders, we evaluated respiratory chain (RC) complexes using mitochondria extracted from biopsy specimens. Through gene and biochemical analyses, including blue-native polyacrylamide gel electrophoresis (BN-PAGE), to evaluate huge RC complexes, we were able to establish diagnoses in numerous patients. For example, we identified the first patient in Japan who had an abnormality in the protein NDUFAF3, which is involved in the assembly process of complex Ⅰ; BN-PAGE demonstrated marked reduction of complex Ⅰ in this patient. Moreover, we discovered mutations in the novel causative gene COX6A2 in two undiagnosed cases; BN-PAGE with muscle biopsy specimens revealed quantitative reductions of complex Ⅳ and its abnormal assembly in these cases. Thus, this study demonstrates the usefulness of evaluating the amount and assembly process of RC complexes in the diagnosis and pathological analysis of mitochondrial disorders.
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| Free Research Field |
小児科学
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| Academic Significance and Societal Importance of the Research Achievements |
ミトコンドリア病の約半数の病因が不明な状況下で、未診断患者の呼吸鎖複合体の量的・質的解析により、新規の病因遺伝子や、未報告の変異を見出すことができた。ミトコンドリア病診断においては、次世代シーケンサーの利用により診断率が上がっているが、遺伝子解析と機能解析を組み合わせることにより診断率をさらに向上させることが可能であることが示された。診断の確定は疾患への対応法や予後に関する情報を患者やその家族に提供することを可能とした。また、遺伝子変異が与える呼吸鎖酵素への影響を明らかにしたことは、病態解析と病因に応じた治療法開発にも寄与するものと考える。
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