■人类促甲状腺激素(TSH)受体(TSHR)基因的遗传缺陷可导致先天性甲状腺功能减退症(CH)。然而,与CH相关的大多数TSHR变异体的生物学功能和全面的基因型-表型关系仍未被研究.我们旨在鉴定中国CH患者的TSHR变异,分析变体的功能,并探讨TSHR基因型与临床表型的关系。
■总共,使用全外显子组测序招募367名CH患者进行TSHR变异筛查。通过例如SIFT和polyphen2的计算机程序评估变体的效果。此外,将这些变体转染到293T细胞中以检测它们的Gs/环状AMP和Gq/11信号活性。
■在367名CH患者中,17种TSHR变体,包括三个新颖的变体,在45名患者中被确认,18例患者携带双等位基因TSHR变异体。体外实验表明,10种变异与Gs/cycleAMP和Gq/11信号通路受损程度不同有关。与具有DUOX2双等位基因变异的患者相比,具有TSHR双等位基因变异的患者在诊断时具有较低的血清TSH水平和较高的游离三碘甲状腺原氨酸和甲状腺素水平。
■我们发现中国CH患者中TSHR变异的频率很高(12.3%),4.9%的病例是由TSHR双等位基因变异引起的。十个变体被鉴定为功能丧失变体。数据表明,由TSHR双等位基因变异引起的CH患者的临床表型相对温和。我们的研究扩展了TSHR变异谱,并为阐明CH的遗传病因提供了进一步的证据。
UNASSIGNED: Genetic defects in the human thyroid-stimulating hormone (TSH) receptor (TSHR) gene can cause congenital hypothyroidism (CH). However, the biological functions and comprehensive genotype-phenotype relationships for most TSHR variants associated with CH remain unexplored. We aimed to identify TSHR variants in Chinese patients with CH, analyze the functions of the variants, and explore the relationships between TSHR genotypes and clinical phenotypes.
UNASSIGNED: In total, 367 patients with CH were recruited for TSHR variant screening using whole-exome sequencing. The effects of the variants were evaluated by in-silico programs such as SIFT and polyphen2. Furthermore, these variants were transfected into 293T cells to detect their Gs/cyclic AMP and Gq/11 signaling activity.
UNASSIGNED: Among the 367 patients with CH, 17 TSHR variants, including three novel variants, were identified in 45 patients, and 18 patients carried biallelic TSHR variants. In vitro experiments showed that 10 variants were associated with Gs/cyclic AMP and Gq/11 signaling pathway impairment to varying degrees. Patients with TSHR biallelic variants had lower serum TSH levels and higher free triiodothyronine and thyroxine levels at diagnosis than those with DUOX2 biallelic variants.
UNASSIGNED: We found a high frequency of TSHR variants in Chinese patients with CH (12.3%), and 4.9% of cases were caused by TSHR biallelic variants. Ten variants were identified as loss-of-function variants. The data suggest that the clinical phenotype of CH patients caused by TSHR biallelic variants is relatively mild. Our study expands the TSHR variant spectrum and provides further evidence for the elucidation of the genetic etiology of CH.