特发性低促性腺激素性性腺功能减退症FGFR1与CEP290基因变异研究

doi:10.16288/j.yczz.22-196

遗传 ›› 2022, Vol. 44 ›› Issue (10): 937-949.doi: 10.16288/j.yczz.22-196

特发性低促性腺激素性性腺功能减退症FGFR1与CEP290基因变异研究

王姗姗¹(), 赵琬怡², 吴慧潇², 舒梦², 袁嘉欣², 方丽², 徐潮¹()

1. 山东第一医科大学附属山东省立医院内分泌与代谢性疾病科,山东省临床医学研究院内分泌代谢研究所,山东省内分泌与脂质代谢重点实验室,济南 250021
2. 山东大学附属山东省立医院内分泌与代谢性疾病科,山东省临床医学研究院内分泌代谢研究所,山东省内分泌与脂质代谢重点实验室,济南 250021

收稿日期:2022-06-15 修回日期:2022-09-17 出版日期:2022-10-20 发布日期:2022-09-29
通讯作者: 徐潮 E-mail:593603071@qq.com;doctorxuchao@163.com
作者简介:王姗姗,在读硕士研究生,专业方向：内分泌与代谢遗传学。E-mail: 593603071@qq.com
基金资助:
国家自然科学基金项目(81974124);泰山学者项目专项资金(20161071)

Research on the variants of FGFR1 and CEP290 genes in idiopathic hypogonadotropin hypogonadism

Shanshan Wang¹(), Wanyi Zhao², Huixiao Wu², Meng Shu², Jiaxin Yuan², Li Fang², Chao Xu¹()

1. Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Institute of Endocrinology, Shandong Academy of Clinical Medicine, Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 2500212, China
2. Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong University, Institute of Endocrinology, Shandong Academy of Clinical Medicine, Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China

Received:2022-06-15 Revised:2022-09-17 Online:2022-10-20 Published:2022-09-29
Contact: Xu Chao E-mail:593603071@qq.com;doctorxuchao@163.com
Supported by:
the National Natural Science Foundation of China(81974124);the Special Funds for the Taishan Scholar Project(20161071)

摘要/Abstract

摘要：

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。

关键词: 特发性低促性腺激素性性腺功能减退症, FGFR1, CEP290, 生物信息学分析

Abstract:

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.

Key words: IHH, FGFR1, CEP290, bioinformatics analysis

王姗姗, 赵琬怡, 吴慧潇, 舒梦, 袁嘉欣, 方丽, 徐潮. 特发性低促性腺激素性性腺功能减退症FGFR1与CEP290基因变异研究[J]. 遗传, 2022, 44(10): 937-949.

Shanshan Wang, Wanyi Zhao, Huixiao Wu, Meng Shu, Jiaxin Yuan, Li Fang, Chao Xu. Research on the variants of FGFR1 and CEP290 genes in idiopathic hypogonadotropin hypogonadism[J]. Hereditas(Beijing), 2022, 44(10): 937-949.

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参数	结果
发病年龄	9月龄
临床症状
生殖系统发育异常	+
嗅觉异常	-
听力丧失	-
骨骼发育不良	-
牙齿发育不良	-
腭裂	-
斜视	+
睾丸体积	0.8 cm×0.5 cm×0.7 cm(左侧) 0.7 cm×0.5 cm×0.6 cm(右侧)
实验室检查
基线FSH (mIU/mL)	0.96(1.27~19.26)
基线LH (mIU/mL)	0.39(1.24~8.62)
基线睾酮 (ng/mL)	0.01(<8.8)
基线PRL (ng/mL)	12.67(2.64~13.13)
曲普瑞林兴奋试验
FSH (30 min) (mIU/mL)	10.56
FSH (60 min) (mIU/mL)	11.22
LH (30 min) (mIU/mL)	2.12
LH (60 min) (mIU/mL)	2.02
脑垂体MRI检查	垂体MR平扫未见明显异常。
生殖系统超声检查	双侧隐睾、双侧腹股沟区探及睾丸回声;双侧睾丸偏小

突变基因	Mutation-Taster		PolyPhen-2
突变基因	分数	结果	分数	结果
FGFR1(c.2008G>A)	-	D	1.000	D
CEP290(c.964G>A)	-	D	0.997	D

特发性低促性腺激素性性腺功能减退症FGFR1与CEP290基因变异研究

Research on the variants of FGFR1 and CEP290 genes in idiopathic hypogonadotropin hypogonadism

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[2]	李晓旭, 刘成, 李伟, 张增林, 高晓明, 周慧, 郭永峰. 番茄WOX转录因子家族的鉴定及其进化、表达分析[J]. 遗传, 2016, 38(5): 444-460.
[3]	杨姗姗，孙晓丽，于洋，才华，纪巍，柏锡，朱延明. 酵母双杂交筛选与GsCBRLK相互作用的蛋白质[J]. 遗传, 2013, 35(3): 388-394.
[4]	傅天韵，娄维义，石铁流. 不同宿主H1N1病毒血凝素蛋白(HA)受体结合位点的变异特征[J]. 遗传, 2010, 32(7): 701-711.
[5]	李志勇，郝志敏，董志平，司贺龙，董金皋 . 玉米大斑病菌钙调磷酸酶A亚基的克隆与特征分析[J]. 遗传, 2009, 31(10): 1059-1064.
[6]	李明，赵巧辉，陈其新，刘孟洲，石晓卫. 家兔BMP7基因的克隆及其生物信息学分析[J]. 遗传, 2008, 30(7): 885-892.