GENETICS OF REPRODUCTION NEUROENDOCRINOLOGY

了解生殖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。特发性促性腺功能减退症（IHH）是一种人类疾病，性成熟的神经内分泌成分在面对低水平的促性腺激素时发生选择性失败，没有任何明显的解剖原因。这种情况的相当大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，IHH患者可以被视为“自然实验”，其中可以发现一系列人类特有的基因突变和生殖关键基因突变。利用临床调查和表型分析、生化分析、经典遗传研究和新的基因组工具，本提案计划利用几种独特的资源来解决这一问题。在过去的25年里，PI已经收集了广泛的这些疾病患者的仔细分析，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，我们将在这一人群中筛选已知在少数IHH病例中导致这种情况的3个基因（KAL， DAX和GnRH/rec）。随后，使用迭代表型，它们的完整生物谱将在第二个目标中定义。然后，高通量筛选技术将用于检查该群体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，连锁分析和基因组错配扫描（GMS）将用于已知常染色体隐性遗传的IHH家族。总之，这种资源和方法的结合应该提供一个独特的机会来获得GnRH和促性腺激素在人类分泌的遗传控制的生物学见解。

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.