SEMA4D基因突变在孤立性促性腺激素释放激素缺乏症发病中的作用及机制研究

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a genetically heterogeneous disease which is caused by defects in the secretion of GnRH or its action and characterized by inappropriately low serum concentrations of the gonadotropins, and is a curable form of male infertility. However, only half of the genes causing IGD have been identified, with a number of genes yet to be discovered. For the past ten years, we have established sample database of nearly 300 IGD patients. We have sequenced 27 identified pathogenic IGD genes and 58 candidate genes in 216 cases by target area next-generation sequencing. Mutations in SEMA4D have been identified, which causes inherited GnRH deficiency. Studies showed SEMA4D regulates gonadotropin hormone –releasing hormone-1 neuronal migration through PlexinB1 –Met complex, but the role of SEMA4D in IGD is also not clear. In this project, we will identify the role and mechanism of SEMA4D in IGD by functional analysis of cell models in vitro and SEMA4D deficient mice model in vivo. In addition, we will identify the frequency of SEMA4D mutations in male Chinese IGD patients and associate the mutation gene with the phenotypes and treatment outcomes, which will be beneficial to the diagnoses, treatment and genetic counselling of IGD.

孤立性促性腺激素释放激素缺乏症（IGD）是因GnRH分泌不足或作用缺陷导致以血促性腺激素下降为特征的遗传异质性罕见病，表现为生殖系统发育异常，部分患者经恰当治疗可获得青春发育及生育。50%以上的致病基因尚未鉴定。申请者经数十年的积累，建立了国内较大的IGD样本库，采用深度测序技术对216例样本的85个已知/候选基因进行测序，并通过生物信息学分析发现SEMA4D基因突变与IGD相关。有研究证实SEMA4D可调节GnRH神经元的迁移，但SEMA4D在IGD中的作用及发病机制不明确。本研究将在前期工作基础上，继续增加IGD样本量，鉴定SEMA4D基因在男性IGD患者中的突变频率，分析该基因突变与临床表型和治疗转归的关系，探讨SEMA4D在IGD中的作用，并利用体外功能实验及基因定点诱变小鼠模型初步阐明SEMA4D在IGD中的发病机制。本研究将为IGD患者的临床诊断、个性化治疗及遗传咨询提供依据。

研究表明孤立性促性腺激素释放激素缺乏症（IGD）是因GnRH分泌不足或作用缺陷导致以血促性腺激素下降为特征的遗传异质性罕见病，表现为生殖系统发育异常，部分患者经恰当治疗可获得青春发育及生育。50%以上的致病基因尚未鉴定。申请者经数十年的积累，建立了国内较大的IGD样本库，采用深度测序技术对216例样本的85个已知/候选基因进行测序，并通过生物信息学分析发现SEMA4D基因突变与IGD相关。通过体外、体内试验我们验证SEMA4D-Ala515Val突变是一个功能损害性突变，通过降低SEMA4D/Plexinb1/Met/RhoA/Raf/MAPK通路活性，抑制GN11细胞迁移。动物试验也验证敲除Sema4d基因后，迁移到下丘脑的GnRH神经元数量减少。但小鼠的血清睾酮水平，生殖系统发育以及精液分析均无明显差异。这也与IHH寡基因致病性相一致。通过此项研究，我们发现并初步验证IHH的一个新的致病基因SEMA4D，以及该基因的一个致病性突变位点SEMA4D-Ala515Val。扩大了IHH致病基因谱，为IHH的基因诊断及个性化治疗提供理论依据。

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