2019 Fiscal Year Final Research Report
Identification of the germline-derived GNAS gain-of-function mutations and clarification of the novel mechanism leading to GNAS loss-of-function
| Project/Area Number |
17H04204
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
OGATA TSUTOMU 浜松医科大学, 医学部, 教授 (40169173)
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| Co-Investigator(Kenkyū-buntansha) |
深見 真紀 国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 部長 (40265872)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | GNAS / 抗利尿不適合性腎症候群 / 機能亢進 / 偽性副甲状腺機能低下症 / 機能低下 |
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| Outline of Final Research Achievements |
GNAS-Gsa mediates signal transductions of multiple G-protein-coupled receptors. It is biallelically expressed in most tissues including the renal collecting duct and is predominantly expressed from the maternal allele in a few tissues such as the renal proximal tubule. We performed whole exome sequencing and identified novel p.F68_G70del and p.M255V variants in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD). We further performed protein structural analysis, in vitro functional analysis, and model mouse analysis, successfully demonstrating that both variants have gain-of-functions. This study demonstrates for the first time the presence of germline-derived GOF variants of GNAS-Gsa and establishes a novel Gsα-mediated genetic disease. We also identified for the first time that elongation of the GNAS region and insertion of retrotransposon can lead to pseudohypoparathyroidism type Ib.
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| Free Research Field |
小児内分泌学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の成果は、第1に世界で初めて生殖細胞由来GNAS-Gsa軽度機能亢進変異の存在を証明し、新規遺伝性疾患を樹立したことにある。さらに、この機能亢進にたいしてAVPR2が最も感受性であること、この変異が体細胞由来高度機能変異で生じるMcCune-Albright症候群を発症しないことも明らかとなった。また、常染色体優性の偽性副甲状腺機能低下症は、STX16欠失を伴うA/B-DMRの低メチル化で生じることが知られていたが、本研究で初めてGNAS領域のゲノム伸展やSVA 型レトロトランスポゾン挿入によっても発症することが示された。これらの成果は、GNAS-Gsaの研究を促進させるものである。
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