Elucidation of the molecular pathogenesis of genetic disorders caused by defects in DNA damage response using deep proteomic analysis

2021 Fiscal Year Final Research Report

• Project/Area Number: 18H03372
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: Nagoya University
• Principal Investigator: Oka Yasuyoshi 名古屋大学, 環境医学研究所, 講師 (60762383)
• Co-Investigator(Kenkyū-buntansha): 荻 朋男 名古屋大学, 環境医学研究所, 教授 (80508317)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: DNA損傷応答システム / ゲノム不安定性 / 遺伝性疾患 / プロテオーム解析 / 疾患ゲノム解析 / マルチオミクス解析

Outline of Final Research Achievements

DNA damage response is prerequisite for the maintenance of genomic stability. Mutations in genes encoding many components of DNA damage response can result in a number of genetic disorders. Recent extensive studies using NGS analysis identify pathogenic mutations in patients with genomic instability. Because the average healthy person has dozens of genetic variants predicted to severely disrupt protein-coding genes, known as loss-of-function variants, and WES is not able to detect chromosomal translocations, large chromosomal deletions and non-canonical splicing mutations, it is difficult to narrow down and identify pathogenic mutations from patients with extremely rare genetic diseases using only NGS technologies. Using deep proteome analysis, we found the novel disease-causing mutation in the RNASEH2B gene from the patient with microcephaly, cerebral atrophy, and basal ganglia calcification, who was undiagnosed using a WES analysis.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、全エキソーム解析のみでは疾患発症因子の同定に至らなかった症例について、プロテオーム解析を実施することで、原因因子を特定することが可能となった。全エキソーム解析に加えて、全ゲノム解析、RNAシーケンス解析、本研究で実施したプロテオーム解析を組み合わせた、マルチオミクス解析を実施することにより、診断率の向上ならびに未診断遺伝性疾患の病態解明へと繋がることが期待される。