OBJECTIVE To characterize the clinical features of a female patient with isolated follicle-stimulating hormone (FSH) deficiency and to investigate the underlying mechanisms of FSH inactivation. METHODS The proband was a 29-year-old woman with primary amenorrhea, impaired pubertal development, and infertility. Subsequently, reproductive endocrine was screened. DNA sequencing was conducted for the identification of FSHβ mutation. RT-PCR, western blots, in vitro immunometric assay, and bioassay were performed to confirm the impact of the mutation on FSH expression and biological activity. Molecular model consisting of FSHα and mutant FSHβ subunit was built for the structural analysis of FSH protein. RESULTS The evaluation of reproductive endocrine revealed undetectable basal and GnRH-stimulated serum FSH. Sequencing of the FSHβ gene identified a homozygous nonsense mutation at codon 97 (Arg97X). RT-PCR and western blot analysis revealed the mutation Arg97X did not affect FSHβ mRNA and protein expression. But in vitro immunometric assay and bioassay demonstrated the production of normal bioactive FSH protein was disturbed by the mutation Arg97X. Structural analysis showed the surface structure of the resulting mutant FSH presented with lock-and-key, mosaic binding pattern, while the native structure was an encircling binding mode. CONCLUSION The mutation Arg97X could disturb structural stability of the resulting FSH protein consisting of FSHα and mutant FSHβ subunit, which may lead to FSH deficiency.

中文翻译：

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孤立的促卵泡激素缺乏女性患者的临床和遗传分析。

目的 描述孤立性促卵泡激素（FSH）缺乏症女性患者的临床特征，并探讨 FSH 失活的潜在机制。方法 先证者是一名 29 岁女性，患有原发性闭经、青春期发育受损和不孕症。随后，进行生殖内分泌筛查。进行 DNA 测序以鉴定 FSHβ 突变。采用 RT-PCR、蛋白质印迹、体外免疫测定和生物测定来确认突变对 FSH 表达和生物活性的影响。建立了由FSHα和突变型FSHβ亚基组成的分子模型，用于FSH蛋白的结构分析。结果 生殖内分泌评估显示基础和 GnRH 刺激的血清 FSH 检测不到。FSHβ 基因测序发现密码子 97 (Arg97X) 处存在纯合无义突变。RT-PCR和蛋白质印迹分析显示Arg97X突变不影响FSHβ mRNA和蛋白表达。但体外免疫测定和生物测定表明正常生物活性FSH蛋白的产生受到Arg97X突变的干扰。结构分析表明，所得突变FSH的表面结构呈现锁钥匙、马赛克结合模式，而天然结构是环绕结合模式。结论 Arg97X 突变可扰乱由 FSHα 和突变 FSHβ 亚基组成的 FSH 蛋白的结构稳定性，从而可能导致 FSH 缺乏。