A novel pathogenic mechanism of delayed myelination caused by deficit of mitochondrial small RNA

Research Project

Project/Area Number	16K19625
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Pediatrics
Research Institution	Tohoku University
Principal Investigator	Ichinoi Natsuko 東北大学, 大学病院, 特任助手 (40509402)
Project Period (FY)	2016-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000) Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords	低分子RNA / 髄鞘化障害 / 先天性大脳白質形成不全 / ミトコンドリア / 先天性大脳白質形成異常 / ミトコンドリア機能障害 / CRISPR/Cas9 / 酸素消費速度 / CRISPR/Cas
Outline of Final Research Achievements	We analyzed skin fibroblasts from a patient with delayed myelination who had compound heterozygous mutations in PNPT1. The expression of a mitochondrial small RNA was decreased in the patient’s fibroblasts than in control. In mitochondrial RNA splicing analysis, including Cox1 and Cox2 region, we confirmed the normal splicing process contrary our hypothesis. We showed reduced mitochondrial function in the patient cells by low oxygen consumption rate using the Extracellular Flux Analyzer. We have been trying to generate transgenic mice that have Pnpt1 missense mutation. Deficit of mitochondrial small RNA may be involved in developing delayed myelination.
Academic Significance and Societal Importance of the Research Achievements	多様な遺伝的背景を有する髄鞘化障害を示す疾患群では，これまでミトコンドリア内RNAの翻訳障害が原因とされる一群が知られていた。本研究は，髄鞘化障害を呈する患者の細胞のミトコンドリア内への低分子RNA輸送障害すなわちミトコンドリア内低分子RNA減少と，それに伴うミトコンドリア機能障害を示した。本研究により，髄鞘化障害を呈する疾患において既知の病態機序に加えて，ミトコンドリア内低分子RNAの不足に伴うミトコンドリア機能障害の関与が示唆された。