特发性低促性腺激素性性腺功能减退症的致病机制研究

特发性低促性腺激素性性腺功能减退症（IHH）是由于GnRH神经元缺陷引起的性腺发育不良疾病，男性发病率约为1/4000，女性发病率约为男性的1/5。现已发现30余个IHH相关基因，但这些基因突变仅能解释大约50%的病例。在前期工作中，我们利用全外显子组测序分析了111例IHH患者，初步绘制了中国IHH患者已知基因突变图谱，进行了初步的临床表型--基因型关联分析，并且在细胞水平分析了一些基因突变的功能。另一方面，我们分析了两种不同发育阶段的GnRH神经元细胞的差异表达mRNA和miRNA，筛选了一系列潜在的调节GnRH神经元发育新基因。本项目拟进一步利用全外显子组测序，系统分析超过200名中国IHH患者的基因突变图谱，构建临床表型和基因型的关系，为IHH的遗传诊断奠定基础。同时利用细胞和动物模型，阐明IHH的分子病理机制。我们相信本项目的完成将为IHH的早诊断、早预防、早治疗提供理论支撑。

The idiopathic hypogonadotropic hypogonadism (IHH) is a rare disease caused by deficiency in the hypothalamus-derived gonadotropin-releasing hormone (GnRH), with a prevalence of 1/4000 in males and 1/20000 in females. More than 30 genes have been associated with IHH; however, mutations in all these genes only account for the genetics of ~50% patients, and the underlying genetic basis for many IHH patients is still unknown. In previous studies, we have analyzed the genetic basis of 111 IHH patients using whole exome sequencing and drafted a mutational spectrum of known IHH-associated genes in Chinese IHH patients. We also performed genotype-phenotype association studies on some IHH patients, and studied the functional consequences of some novel mutations at the cellular level. Further, we analyzed the differentially expressed genes in two GnRH neuronal cells from different developmental stages, and identified a panel of novel genes potentially involved in the development of GnRH neurons. In this project, we propose to generate a genetic spectrum for more than 200 Chinese IHH patients by using whole exome sequencing, and analyze the relationship between genotype and phenotype to establish a basis for IHH genetic diagnosis. Moreover, the underlying pathological mechanisms of IHH will be studied at the levels of cell biology and model organism. We believe the completion of this project will improve our understanding on the molecular mechanisms of IHH, and eventually benefit early diagnosis, prevention and treatment.