Role of mitochondrial gene mutations for the development of early-onset familial diabetes

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K07895
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Osaka City General Hospital
• Principal Investigator: YORIFUJI TOHRU 地方独立行政法人大阪市民病院機構大阪市立総合医療センター(臨床研究センター), 臨床研究センター, 部長 (60220779)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: MODY / 遺伝子 / ミトコンドリア

Outline of Final Research Achievements

This is a study focusing on the genetic background of early-onset diabetes in Japan with special attention on the role of mitochondrial DNA variants. (1) For 368 Japanese patients with suspected monogenic diabetes, we performed targeted next generation sequencing of 25 known causative genes, MLPA analysis, PCR-RFLP analysis of mitochondrial m.3243A>G variant, and methylation-specific PCR analysis of the imprinted 6q24 locus. As a result, we identified 156 pathogenic/likely pathogenic variants. In addition, we could identify 44 patients with variants of the population frequency <0.001 and the CADD score >20. (2) We then established the methodology to deep-sequence mitochondrial DNA by using a next-generation sequencer. The analysis was applied to 8 patients without a pathogenic variant by the above mutational analysis and 8 control patients. As a result, we could identify 207 variant loci of heterogeneity. However, there were no locus significantly enriched in the patient group.

Free Research Field

医学

Academic Significance and Societal Importance of the Research Achievements

当初目的とした若年2型糖尿病特有のミトコンドリア遺伝子異常は認めなかったが、研究の過程で我が国における単一遺伝子性糖尿病の頻度、遺伝子スペクトルについて明らかにすることができた。単一遺伝子性糖尿病の治療ストラテジーは一般の1型、2型糖尿病と異なるものがあり、通常の治療を行うことは時に有害であり、患者の不利益につながるばかりか、社会資本の浪費にもつながる。遺伝背景に応じた糖尿病のテーラーメード治療のための基礎データを構築できた。