Identification of novel pathogenic variants caused by defects of interstrand DNA crosslink repair
| Project/Area Number |
16K21084
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Genome biology
Risk sciences of radiation and chemicals
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| Research Institution | Nagoya University |
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Principal Investigator |
OKA Yasuyoshi 名古屋大学, 環境医学研究所, 特任助教 (60762383)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | DNA損傷応答 / DNA修復 / 遺伝性疾患 / ゲノム不安定性 / 疾患モデル動物 / プロテオーム解析 / 造血幹細胞 / 小頭症 |
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| Outline of Final Research Achievements |
The goal in this study is to identify novel pathogenic variants caused by the loss of genome stability from patients with microcephaly. Whole exome sequencing identified possible pathogenic variants in two different aldehyde metabolism-related genes from Japanese patients with short stature, microcephaly and hematological abnormality. To understand the molecular mechanisms by which the digenic variants cause microcephaly and hematological abnormality, we performed cellular experiments using cells derived from patients, knockout cell lines using CRISPR/Cas9-mediated genome editing technology, and umbilical cord blood CD34+ cells. These experiments showed two different aldehyde metabolism-related genes contribute to genome maintenance and hematopoietic homeostasis synergistically because simultaneous loss of function of two aldehyde metabolism-related genes leads to hypersensitivity to genotoxic stress or low differentiation ability of hematopoietic stem and progenitor cells in vitro.
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| Academic Significance and Societal Importance of the Research Achievements |
ゲノム安定化維持機構に異常を持った劣性遺伝性疾患の臨床像として小頭症を呈する患者群に着目し、ICL修復との関連性から新規の原因遺伝子変異を探すというアプローチは前例がなく、斬新である。本研究では、ゲノムの不安定化により発症した新規の劣性遺伝性疾患の発症原因となる候補遺伝子変異を同定しており、小頭症発症の詳細な分子メカニズムの解明に繋がることが期待される。
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Report
(4 results)
Research Products
(15 results)
