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通过基因突变和M453T-knockin模型解读的甲状腺蛋白受体介导的表型变异性机制
Kristiina Makkonen1,2, Meeri Jännäri1,2, Luís Crisóstomo2
1Department of Clinical Sciences, Faculty of Medicine, and.
JCI insight
|January 9, 2024
概括
甲状腺蛋白受体 (TSHR) 变异影响甲状腺疾病的风险和呈现. 遗传变异和摄入量可以改变TSHR介导的疾病表型,需要个性化治疗方法.
科学领域:
- 内分泌学 在内分泌学.
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 甲状腺激素受体 (TSHR) 介导的疾病包括一系列疾病,从先天性甲状腺功能低下症到非自身免疫性甲状腺功能升高症 (NAH).
- 人们对TSHR的甲状腺外功能以及各种疾病表现的原因仍然不太了解.
- TSHR变异与代谢和自身免疫性甲状腺疾病有关,但缺乏全面的分析.
研究的目的:
- 识别和描述TSHR变体和导致TSHR介导疾病表型变异的因素.
- 调查遗传和环境因素在TSHR相关疾病中的作用.
- 探索TSHR疾病不同临床表现背后的机制.
主要方法:
- 对患者队列中TSHR变异的分析和FinnGen数据库.
- 在NAH患者中对新型TSHR构成性活性突变 (CAMs) 的表征.
- 一个TSHR M453T-knockin小鼠模型的生成和研究.
主要成果:
- 在所有NAH患者中确定了TSHR CAM,包括细胞外和膜外域的新突变.
- 芬兰基因数据库的查发现了罕见的功能TSHR变体和与甲状腺表型相关的常见非编码SNP.
- 在TSHR变体和2000多个非甲状腺疾病终点之间没有发现显著的关联.
- 鼠标模型表明,TSHR表型取决于突变信号,并受到摄入的影响.
结论:
- 通过TSHR介导的疾病风险受编码和非编码TSHR变体的影响.
- 改变TSHR信号和摄入量是疾病表型的关键修饰因素.
- 这些发现支持开发针对TSHR相关疾病的个性化治疗策略.
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