GENETICS OF REPRODUCTION NEUROENDOCRINOLOGY

了解生殖的神经内分泌控制的遗传和分子决定因素一直是一个重要但难以捉摸的目标。特发性低促性腺激素性性腺功能减退症（IHH）是一种人类疾病，在没有任何可证实的解剖学原因的情况下，性成熟的神经内分泌成分在低水平的促性腺激素下发生选择性失败。这种疾病的遗传和表型异质性表明，它是一个丰富的独特信息来源，不仅关于生殖的神经内分泌控制，而且关于其他几个器官的发育。因此，患有IHH的患者可以被视为“自然实验”，其中可以发现人类特异性基因和生殖关键基因的一系列突变。利用临床研究和表型分析，生化分析，经典遗传学研究和新的基因组工具，该提案计划使用几种独特的资源来解决这个问题。在过去的25年里，PI已经收集了广泛的患有这些疾病的患者，并建立了一个不断发展的表型和基因型特征数据库以及一个不断增长的血清和DNA样本库。在我们的第一个目标中，将在该人群中筛选已知在少数IHH病例中引起这种疾病的3种基因（KAL，DAX和GnRH/rec）。随后，使用迭代表型分析，将在第二个目标中定义其完整的生物谱。高通量筛选技术将用于检测该人群中广泛的新候选基因及其在第三个目标中类似鉴定的表型。最后，在适当的情况下，将在已知常染色体隐性遗传的IHH家族中进行连锁分析和基因组错配扫描（GMS）。总之，这种资源和方法的结合应该允许一个独特的机会，以获得生物学的见解，在人类的GnRH和促性腺激素分泌的遗传控制。

Understanding the genetic and molecular determinants of the neuroendocrine control of reproduction has been an important but elusive goal. Idiopathic hypogonadotropic hypogonadism (IHH) is a human disorder in which selective failure of the neuroendocrine components of sexual maturation occurs in the face of low levels of gonadotropins without any demonstrable anatomic cause. The considerable genetic and phenotypic heterogeneity of this condition suggests it is a rich source of unique information, not only about the neuroendocrine control of reproduction, but also about the development of several other organs. Thus, patients with IHH can be viewed as 'experiments of nature/ in which a series of mutations in genes both specific for the human and key to reproduction can be discovered. Utilizing clinical investigation and phenotyping, biochemical profiling, classical genetic studies, and new genomic tools, this proposal plans to address this issue using several unique resources. A broad spectrum of carefully profiled patients with these disorders has been assembled by the PI over the past 25 years and an evolving database of their phenotypic and genotypic features as well as a growing repository of their serum and DNA samples has been established. In our 1st aim, the 3 genes already known to cause this condition in a minority of IHH cases (KAL, DAX, and GnRH/rec) will be screened in this population. Subsequently, using iterative phenotyping, their full biologic spectrum will be defined in the 2nd aim. High throughput screening technologies will then be used to examine a wide spectrum of new candidate genes in this population and their phenotypes similarly identified in the 3rd aim. Finally, where appropriate, linkage analysis and genome mismatch scanning (GMS) will be employed in IHH families with known autosomal recessive inheritance. Together, this combination of resources and approaches should permit a unique opportunity to gain biologic insights into the genetic control of both GnRH and gonadotropin secretion in the human.