Multi-layered mutations in patient with Gorlin syndrome may affect the phenotype

Gorlin 综合征患者的多层突变可能影响表型

• 批准号: 21K10103
• 负责人: 小野寺 晶子
• 金额: $ 2.66万
• 依托单位: Tokyo Dental College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2022
• 资助国家: 日本
• 起止时间: 2022-01-04 至 2023-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21K10103/
• 关键词: Gorlin症候群; 疾患iPS細胞; Hedgehog経路; 遺伝子変異; 遺伝子パネル; 多重変異; 診断パネル; ヘッジホッグ

Hedgehog受容体であるPTCH1の機能喪失変異はGorlin症候群を引き起こし、大脳鎌の石灰化、二分肋骨、顎骨内の角化嚢胞など多彩な表現型を生じる。PTCH1の機能喪失変異はヘッジホッグ経路を活性化して様々な病態が生じることが知られている。一方PTCH1の変異部位は一定でなく、各患者の変異部位とヘッジホッグシグナルの活性化やその表現型との関係は未だ明らかでない。この点を明らかにするために、我々はこれまでPTCH1の変異部位の解析に加えて、PTCH1と他のヘッジホッグ受容体であるPTCH2, BOCの多重変異がヘッジホッグシグナル活性を変化させることを明らかにしてきた。本研究では遺伝子解析と疾患iPS細胞を用いた疾患モデルを組み合わせ、Hh受容体群の遺伝子変異で誘導されるHhシグナル活性化レベルの違いを明らかにし、シグナル活性化レベルと表現型を関連づけ、病気発症に関わるシグナルレベルの閾値を明らかにする。Hh受容体群の多重遺伝子変異の解析により病態発生機構を解明することを目的とする。我々のグループはGolrin症候群患者の責任遺伝子となりうるPTCH1,PTCH2,SMO, SUFUを一度に解析可能な遺伝子パネルを作成した。またこのパネルを使用しGolrin症候群患者の遺伝子変異解析を行い、複数名の患者からPTCH1,PTCH2に変異が確認されたことを報告している。またExomeシークエンスを用いて同一患者に多発性に生じた歯原生角化嚢胞、基底細胞癌における遺伝子変異を報告した。

Hedgehog receptor loss of PTCH1 function varies from Gorlin syndrome to calcification, bisection of ribs, keratinization of cells in jaw bone, and multicolored phenotype. It is now known that PTCH1 has lost its function and become active in the fiber optic cable, causing morbidity. The different sites of PTCH1 in a single patient are different, and the relationship between the different sites of PTCH1 and the phenotype of PTCH1 is not clear. The analysis of different parts of PTCH1, PTCH 2, BOC and their different parts of PTCH1, BOC and their different parts of PTCH2, BOC and their different parts of PTCH1, BOC and their different parts of PTCH2, BOC and their different parts of In this study, we identified the association between gene analysis and the use of iPS cells in the treatment of diseases, the association between gene expression and phenotype, the association between disease development and threshold values, and the induction of gene differentiation in Hh receptor populations. The analysis of multiple genetic diversity of Hh receptor groups is aimed at understanding the mechanism of pathological development. We are responsible for the development of PTCH1,PTCH2,SMO and SUFU in patients with Golrin syndrome. The use of this method in the analysis of genetic differences in patients with Golrin syndrome, multiple patients with PTCH1,PTCH2, and identification of genetic differences in patients with Golrin syndrome is reported. Exome treatment is used to treat multiple tumors in the same patient, including primary keratinocytes and basal cell carcinomas.

项目成果

Induced pluripotent stem cells from homozygous Runx2-deficient mice show poor response to vitamin D during osteoblastic differentiation

• DOI: 10.1007/s00795-022-00317-w
• 发表时间: 2022-04
• 期刊: Medical Molecular Morphology
• 影响因子: 1.8
• 作者: H. Aoki;E. Suzuki;Takashi Nakamura;Shoko Onodera;A. Saito;M. Ohtaka;M. Nakanishi;K. Nishimura;Atsushi Saito;Toshifumi Azuma

Development of a targeted gene panel for the diagnosis of Gorlin syndrome

• DOI: 10.1016/j.ijom.2022.03.054
• 发表时间: 2022-10-31
• 期刊: INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY
• 影响因子: 2.4
• 作者: Nakamura，Y.;Onodera，S.;Azuma，T.
• 通讯作者: Azuma，T.