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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism
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Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism

机译：成纤维细胞生长因子受体1的突变会引起Kallmann综合征和常态性特发性性腺功能减退性腺功能减退

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摘要

Mutations in KAL1 and FGFR1 cause Kallmann syndrome (KS), whereas mutations in the GNRHR and GPR54 genes cause idiopathic hypogonadotropic hypogonadism with normal olfaction (nIHH). Mixed pedigrees containing both KS and nIHH have also been described; however, the genetic cause of these rare cases is unknown. We examined the FGFR1 gene in seven nIHH subjects who either belonged to a mixed pedigree (n = 5) or who had associated midline defects (n = 2). Heterozygous FGFR1 mutations were found in three of seven unrelated nIHH probands with normal MRI of the olfactory system: (i) G237S in an nIHH female and a KS brother; (it) (P722H and N724K) in an nIHH male missing two teeth and his mother with isolated hyposmia; and (iii) Q68OX in a nIHH male with cleft lip/palate and missing teeth, his brother with nIHH, and his father with delayed puberty. We show that these mutations lead to receptor loss-of-function. The Q680X leads to an inactive FGFR1, which lacks a major portion of the tyrosine kinase domain (TKD). The G237S mutation inhibits proper folding of D2 of the FGFR1 and likely leads to the loss of cell-surface expression of FGFR1. In contrast, the (P722H and N724K) double mutation causes structural perturbations in TKD, reducing the catalytic activity of TKD. We conclude that loss-of-function mutations in FGFR1 cause nIHH with normal MRI of the olfactory system. These mutations also account for some of the mixed pedigrees, thus challenging the current idea that KS and nIHH are distinct entities.
机译：KAL1和FGFR1中的突变会引起Kallmann综合征（KS），而GNRHR和GPR54基因中的突变会导致特发性促性腺激素减退性腺功能减退，嗅觉正常（nIHH）。还描述了同时包含KS和nIHH的混合血统书。然而，这些罕见病例的遗传原因尚不清楚。我们检查了7个nIHH受试者的FGFR1基因，这些受试者属于混合谱系（n = 5）或具有相关的中线缺陷（n = 2）。在嗅觉系统MRI正常的七个不相关的nIHH先证者中，有三个发现杂合FGFR1突变：（i）nIHH女性和KS兄弟中的G237S； （it）（P722H和N724K）在一名nIHH男性中缺失了两颗牙齿，其母亲患有孤立性低渗症； （iii）Q68OX在一位nIHH男性（唇裂/颚裂且牙齿缺失），他的nnHH男性兄弟以及其青春期延迟的父亲中。我们表明，这些突变导致受体功能丧失。 Q680X导致FGFR1失活，而FGFR1缺乏酪氨酸激酶结构域（TKD）的主要部分。 G237S突变抑制FGFR1 D2的正确折叠，并可能导致FGFR1细胞表面表达的丧失。相反，（P722H和N724K）双重突变会导致TKD中的结构扰动，从而降低TKD的催化活性。我们得出结论，在嗅觉系统正常MRI中，FGFR1的功能丧失突变会引起nIHH。这些突变也说明了某些混合的血统，从而挑战了当前的观点，即KS和nIHH是不同的实体。

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