在367名患有先天性甲状腺功能低下症的中国患者中进行变异查和表型分析
Hai-Yang Zhang1, Feng-Yao Wu1, Xue-Song Li2
1The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Annals of laboratory medicine
|March 4, 2024
概括
甲状腺刺激激素受体 (TSHR) 基因中的遗传缺陷是先天性甲状腺功能低下症 (CH) 的原因之一. 这项研究在中国CH患者中确定了TSHR变异,揭示了功能丧失变异的显著频率和较温和的临床表型.
科学领域:
- 内分泌学 在内分泌学.
- 遗传学 遗传学 是一个
- 分子生物学分子生物学
背景情况:
- 甲状腺刺激激素 (TSH) 受体 (TSHR) 基因的遗传缺陷是已知的先天性甲状腺功能低下症 (CH) 的原因之一.
- 在CH中,许多TSHR变异的综合基因型-表型关系和生物功能仍然在很大程度上未被描述.
- 了解这些变体对于诊断和管理CH至关重要.
研究的目的:
- 在被诊断为CH的中国患者中识别TSHR变异.
- 分析已识别的TSHR变异对信号通路的功能影响.
- 探索具有TSHR变异的CH患者的基因型-表型相关性.
主要方法:
- 对367名CH患者进行全外体序列测序,以选TSHR变异.
- 使用in silico预测工具 (SIFT,polyphen2) 来评估变种的致病性.
- 在293T细胞中进行了功能测试,以评估TSHR变体的Gs/循环AMP和Gq/11信号活动.
主要成果:
- 在367名CH患者中,在45名患者中发现了17种TSHR变异,其中包括3种新型变异;18名患者有双性TSHR变异.
- 实验室研究表明,10种变体在不同程度上损害了TSHR信号通路 (Gs/循环AMP和Gq/11).
- 与DUOX2变种患者相比,双性TSHR变种患者在诊断时表现出较低的TSH和较高的自由三甲状腺素/甲状腺素水平.
结论:
- 在中国CH患者中,TSHR变异很常见 (12.3%),双变异占4.9%的病例.
- 十个已识别的TSHR变异被归类为功能丧失,这表明它在CH病因学中起着重要作用.
- 由双性TSHR变体引起的CH似乎呈现出相对温和的临床表型,扩大了已知的CH遗传原因.
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