• PMID: 29777911
• Gene Name: GNRHR
• Condition: Idiopathic hypogonadotropic hypogonadism
• Association: Associated
• Mutation: c.364C>T, p.L122F
• Population size: 3
• Population details: 3 cases
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Deficiency in GnRH receptor trafficking due to a novel homozygous mutation causes idiopathic hypogonadotropic hypogonadism in three prepubertal siblings

Zhang R, Linpeng S, Li Z, Cao Y, Tan H, Liang D, Wu L.

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by low levels of gonadotropins and delayed or absent sexual development. Most of the patients are diagnosed in late adolescence or early adulthood. Determining the diagnosis of IHH in prepubertal patients can be challenging. Making a timely, correct diagnosis has important clinical implications. Here we aimed to identify the genetic cause of IHH in three prepubertal siblings from a Chinese Han family and give appropriate treatment advice. Using whole exome sequencing (WES), we identified a novel homozygous GNRHR mutation (NM_000406; c.364C>T, p.L122F) in two prepubertal boys with cryptorchidism and micropenis. Sanger sequencing showed that their younger asymptomatic sister also had the homozygous GNRHR mutation. This mutation was inherited from the father and the mother. Immunofluorescence analysis showed that in permeabilized cells, expression of the mutant receptor on the cell membrane was significantly lower than that of wild-type. Calcium mobilization assays demonstrated that c.364C>T in the GNRHR gene is a complete loss-of-function mutation that caused IHH. These results may contribute to the genetic diagnosis of the three prepubertal siblings with IHH. According to this diagnosis, timely hormonal treatment can be given for the three prepubertal patients to induce pubertal development, especially for the asymptomatic female. CI - Copyright © 2018 Elsevier B.V. All rights reserved. FAU - Zhang, Rui AU - Zhang R AD - Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China; Department of Prenatal Diagnosis, Bao'an Maternity and Child Health Hospital, Shenzhen, China. FAU - Linpeng, Siyuan AU - Linpeng S AD - Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China. FAU - Li, Zhuo AU - Li Z AD - Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China. FAU - Cao, Yingxi AU - Cao Y AD - Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China. FAU - Tan, Hu AU - Tan H AD - Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China. FAU - Liang, Desheng AU - Liang D AD - Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China. Electronic address: liangdesheng@sklmg.edu.cn.