Novel FSHR variants causing female resistant ovary syndrome
Novel FSHR variants causing female resistant ovary syndrome
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导致女性抵抗性卵巢综合征的新型 FSHR 变异
DOI：
10.1002/mgg3.1082
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发表时间：
2019-12-12
影响因子：
2
通讯作者：
Lu, Xuefeng
中科院分区：
文献类型：
--
作者：
Khor, Shuzin;Lyu, Qifeng;Lu, Xuefeng
背景促卵泡激素受体（FSHR）的致病性变异体可导致女性闭经和不孕。然而，只有有限数量的致病性FSHR变异已被报道，很少有报告描述了致病性FSHR变异患者的详细特征。方法对患病同胞及父母进行全基因组外显子测序。用构建的载体进行HEK 293 T细胞的瞬时转染。使用共聚焦显微镜评估FSHR蛋白的细胞定位，并且使用cAMP ELISA试剂盒检测环磷酸腺苷（cAMP）的产生。结果一个FSHR复合杂合致病性突变c.182T>A（p.Ile61Asn）和c.2062C>A（p.Pro688Thr）家系。两个兄弟姐妹都有闭经、不孕和对促性腺激素（Gn）刺激的抵抗，但显示出高抗苗勒管激素水平和早期窦状卵泡。FSHR变体的分子动力学模拟揭示了结构特征和静电势的显着变化。体外分析表明，p.Ile61Asn变体缺乏细胞表面定位，并完全取消了cAMP第二信使反应。p.Pro688Thr变体保留了细胞表面定位，但导致FSH诱导的cAMP产生减少。结论我们发现了两种新的致病性FSHR变异体引起抵抗性卵巢综合征。本研究扩展了致病性FSHR变异体的基因型谱和我们对表型-基因型相关性的认识。
Background Pathogenic variants of follicle-stimulating hormone receptor (FSHR) are known to cause amenorrhea and infertility in women. However, only a limited number of pathogenic FSHR variants have been reported, and few reports described detailed characteristics of patients with pathogenic FSHR variants. Methods The affected siblings and both parents were subjected to whole-genome exon sequencing. Transient transfection of HEK 293T cells was performed with constructed vectors. The cellular localization of the FSHR protein was evaluated using confocal microscopy, and cyclic adenosine monophosphate (cAMP) production was detected with a cAMP ELISA kit. Results A Chinese family with two siblings carrying compound heterozygous pathogenic variants of FSHR: c.182T>A (p.Ile61Asn) and c.2062C>A (p.Pro688Thr). Both siblings had amenorrhea, infertility, and resistance to gonadotropin (Gn) stimulation but showed high anti-Mullerian hormone levels and early antral follicles. Molecular dynamics simulations of the FSHR variants revealed significant changes in structural characteristics and electrostatic potential. In vitro analysis indicated that the p.Ile61Asn variant lacked cell surface localization and completely abolished the cAMP second messenger response. The p.Pro688Thr variant retained cell surface localization but caused decreased FSH-induced cAMP production. Conclusion We found two novel pathogenic FSHR variants causing resistant ovarian syndrome. This study expands the genotypic spectrum of pathogenic FSHR variants and our knowledge of phenotype-genotype correlations.