A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor
A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor
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DOI：
10.1172/jci3795
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发表时间：
1998-10-01
影响因子：
15.9
通讯作者：
Misrahi, W
中科院分区：
文献类型：
--
作者：
Beau, I;Touraine, P;Misrahi, W
迄今为止，已经描述了促卵泡激素受体（FSHR）的单个自然功能丧失突变。在芬兰人群中，它明显损害受体功能，在初级阶段阻断卵泡发育，表现为原发性闭经伴卵巢萎缩。当西欧妇女与这种表型进行检查FSHR突变的结果是阴性的，这表明其他病因相应的这种临床模式是显着更frequent.We现在描述一种新的表型相关的突变引起的FSHR的功能部分丧失。继发性闭经的妇女有非常高的血浆促性腺激素浓度（尤其是FSH），与正常大小的卵巢和窦卵泡在超声检查高达5毫米。卵巢的组织学和免疫组织化学检查显示正常卵泡发育到小窦阶段，并在进一步的阶段中断。发现患者携带FSHR基因的复合杂合突变：Ile 160 Thr和Arg 573 Cys取代分别位于受体的细胞外结构域和第三胞内环。突变的受体，当在COS-7细胞中表达时，表现出部分功能障碍，与临床和组织学观察一致：第一个突变损害细胞表面表达和第二个改变的信号转导的receptor.This观察表明，有限的FSH作用足以促进卵泡生长到小窦阶段。进一步的发展需要强烈的FSH刺激。因此，非常高的FSK水平和正常大小的卵巢与窦卵泡之间的对比可能是这类患者的特征。
A single natural loss of function mutation of the follicle stimulating hormone receptor (FSHR) has been described to date. Present in the Finnish population it markedly impairs receptor function, blocking follicle development at the primary stage and presenting as primary amenorrhea with atrophic ovaries. When Western European women with this phenotype were examined for FSHR mutations the result was negative, suggesting that other etiologies corresponding to this clinical pattern are markedly more frequent.We now describe a novel phenotype related to mutations provoking a partial loss of function of the FSHR. A woman with secondary amenorrhea had very high plasma gonadotropin concentrations (especially FSH), contrasting with normal sized ovaries and antral follicles up to 5 mm at ultrasonography. Histological and immunohistochemical examination of the ovaries showed normal follicular development up to the small antral stage and a disruption at further stages. The patient was found to carry compound heterozygotic mutations of the FSHR gene: Ile160Thr and Arg573Cys substitutions located, respectively, in the extracellular domain and in the third intracellular loop of the receptor. The mutated receptors, when expressed in COS-7 cells, showed partial functional impairment, consistent with the clinical and histological observations: the first mutation impaired cell surface expression and the second altered signal transduction of the receptor.This observation suggests that a limited FSH effect is sufficient to promote follicular growth up to the small antral stage. Further development necessitates strong FSH stimulation. The contrast between very high FSK levels and normal sized ovaries with antral follicles may thus be characteristic of such patients.