Idiopathic hypogonadotropic hypogonadism (IHH) is a rare endocrine disease characterized by gonadal dysplasia. According to whether the sense of smell is affected, this disorder is classified into Kallmann syndrome (KS) and normosmic isolated hypogonadotropic hypogonadism (nIHH). In this study, we reported a case of nIHH patient and explored the pathogenic mechanism of FGFR1 in nIHH. A FGFR1 variant (c.2008G>A, p.E670K) and a CEP290 variant (c.964G>A, p.D322N) were detected by the whole exome sequencing in this nIHH patient. Bioinformatic analysis revealed that this FGFR1 variant (c.2008G>A) causes structural perturbations in TK2 domain demonstrating that this variant result in FGFR1 loss-of-function and abnormal signaling. The identification of an additional CEP290 variant (c.964G>A) indicated that CEP290 might play a potential role in developmental abnormalities and inhibition of GnRH neuron release. A protein interaction network analysis showed that CEP290 was predicted to interact with FGFR1. In summary, our study identified the potential pathogenic mechanism(s) of the novel FGFR1 variant and indicated that CEP290 might play a role in the GnRH neuron migration route. Our findings expand the mutation spectrum of FGFR1 and CEP290 and provide a reference for clinical diagnosis and treatment of IHH.
特发性低促性腺激素性性腺功能减退症(idiopathic hypogonadotropic hypogonadism, IHH)是由于促性腺激素释放激素(gonadotropin-releasing hormone, GnRH)缺乏或作用缺陷引起以性腺发育不良为特征的内分泌罕见病。依据是否并发嗅觉障碍可以分为嗅觉正常特发性低促性腺激素性性腺功能减退症(normosmic isolated hypogonadotropic hypogonadism, nIHH)和嗅觉障碍的卡尔曼综合征(Kallmann syndrome, KS)。本研究收集并分析了1例nIHH散发病例的临床资料。全外显子测序证实患儿同时携带FGFR1基因变异(c.2008G>A, p.E670K)和遗传于其母亲的CEP290基因变异(c.964G>A, p.D322N)。生物信息学分析发现FGFR1基因突变(c.2008G>A)改变FGFR1蛋白TK2结构域,影响FGFR1受体的功能及下游细胞信号转导通路的激活。CEP290基因(c.964G>A)可能影响GnRH神经元的正确迁徙途径导致IHH,CEP290蛋白与FGFR1蛋白之间存在相互作用。本研究结果扩展了IHH致病基因表达谱,为探究IHH的致病机制提供了新的方向,并为该类疾病的临床精准诊疗提供了借鉴和参考。.
Keywords: CEP290; FGFR1; IHH; bioinformatics analysis.