2022 Fiscal Year Final Research Report
in vivo and in vitro analysis of LRRTM4 mutation associated with dominant-inherited macular degeneration.
| Project/Area Number |
18K09432
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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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| Review Section |
Basic Section 56060:Ophthalmology-related
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| Research Institution | 独立行政法人国立病院機構(東京医療センター臨床研究センター) |
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Principal Investigator |
Okamoto Akiko (須賀) 独立行政法人国立病院機構(東京医療センター臨床研究センター), 分子細胞生物学研究部, 研究員 (70450400)
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| Project Period (FY) |
2018-04-01 – 2023-03-31
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| Keywords | 遺伝性疾患 / 全エクソーム解析 / 全ゲノム解析 / 変異 / 機能解析 / 疾患モデル動物 |
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| Outline of Final Research Achievements |
We examined the pathogenic effect of LRRTM4 p.C538Y variant which was identified as a candidate causal mutation for autosomal dominant macular dystrophy. Mutant mouse with Lrrtm4 p.C538Y missense mutation was tested. While the patients showed severe macular degeneration and loss of ON-bipolar cell responses, the mutant mice did not show significant differences in the retinal thickness and bipolar cell responses from the wild type littermates up to one year. To examine the possible effect of additional genetic variant(s), we performed whole-genome sequencing of the three patients in a family. From more than 25,000 variants, we selected patient-specific variants that located inside gene(s), and found a tandem duplication of several exons in another gene (gene X). Previous reports showed retinal degeneration in mice with conditional gene X depletion, which suggested possible effect of gene X structural variant on macular degeneration.
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| Free Research Field |
遺伝性網膜変性疾患
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| Academic Significance and Societal Importance of the Research Achievements |
症状と家系情報から遺伝性疾患が疑われるにもかかわらず既知遺伝子変異が検出されない患者に対して、全エクソーム解析および全ゲノム解析をすることで疾患と関連する新規原因遺伝子候補を絞り込むことができた。患者のゲノム情報およびバリアント頻度と有害度予測により可能性の高い疾患原因と予想された変異であっても動物モデル等で患者症状を反映する表現型が得られない場合、生物種間の差だけでなくゲノム解析の方法に依存して検出できなかった変異が影響している可能性が示唆された。ゲノム解析で示される疾患原因変異の適切な解釈には実験系による検討が重要と考えられる。
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