Establishing the Genetic Etiology for Kallmann Syndrome

描述（由申请人提供）：在所有哺乳动物物种中，促性腺激素释放激素（GnRH）是复杂生殖级联中的第一种激素。GnRH由下丘脑释放，刺激垂体分泌促黄体激素（LH）和促卵泡激素（FSH）;这些促性腺激素然后刺激性腺产生性类固醇和卵泡/精子。GnRH的作用是复杂的-它是以脉动的方式分泌的，而不是组成性的，时尚的，并且在整个生殖周期中以可变的频率分泌。了解什么信号调节GnRH神经元的发育命运和分泌活动仍然是生殖生物学家的一个主要问题。 这项拨款提案将使用GnRH分泌缺陷或缺失的人类疾病模型来解决这个问题。患有这种疾病的患者，特发性低促性腺激素性性腺功能减退症（IHH），无法进入青春期，如果不治疗，会导致不育。虽然先天性IHH是一种罕见的疾病，家庭规模通常很小，一个大的近交系的法裔加拿大血统已被确定与IHH和嗅觉丧失。已经进行了全基因组扫描，并确定了遗传缺陷的染色体位点。在这个提议中，候选区域将被进一步细化，该区域的完整转录图谱将被开发，并且RT-PCR将被用于筛选精确的基因突变的候选基因。然后将突变谱与患者的基线临床/生化特征、其神经内分泌表型以及其对外源性脉动GnRH生理替代的反应并置，以建立稳健的基因型/表型相关性。将研究基因表达的时空模式，并开发体外模型系统来研究新鉴定基因的生理学。希望这些信息最终将用于了解许多由GnRH分泌异常定义的人类疾病，包括体质性青春期延迟，下丘脑性闭经和中枢性早熟。

DESCRIPTION (provided by applicant): In all mammalian species, gonadotropin-releasing hormone (GnRH) is the first hormone in a complex reproductive cascade. GnRH is released by the hypothalamus and stimulates the secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary; these gonadotropins then stimulate the gonads to produce sex steroids and follicles/sperm. The actions of GnRH are complex--it is secreted in a pulsatile, as opposed to constitutive, fashion, and at variable frequencies throughout the reproductive cycle. Understanding what signals modulate the developmental fate and secretory actions of GnRH neurons remains a major question for reproductive biologists. This grant proposal will address this issue using a human disease model in which GnRH secretion is defective or absent. Patients with this condition, idiopathic hypogonadotropic hypogonadism (IHH), fail to undergo puberty and are infertile if untreated. Although congenital IHH is a rare disease and family sizes are typically small, a large inbred family of French Canadian descent has been identified with IHH and anosmia. A genome wide scan has been performed and a chromosomal locus for the genetic defect has been identified. In this proposal, the candidate region will be further refined, a complete transcript map for the region will be developed, and RT-PCR will be used to screen the candidate gene for the precise genetic mutation. The mutation spectrum will then be juxtaposed against the baseline clinical/biochemical features of the patients, their neuroendocrine phenotypes, as well as their responses to physiologic replacement with exogenous pulsatile GnRH to develop robust genotype/phenotype correlations. The spatiotemporal pattern of expression of the gene will be studied and in vitro model systems developed to study the physiology of the newly-identified gene. It is hoped that this information will ultimately be used to understand numerous human diseases defined by abnormalities in GnRH secretion, including constitutional delay of puberty, hypothalamic amenorrhea, and central precocious puberty.