Establishing the Genetic Etiology for Kallmann Syndrome

建立卡尔曼综合征的遗传病因学

• 批准号: 7409528
• 负责人: Stephanie Beth Seminara
• 金额: $ 36.17万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409528
• 关键词: 15q14; Address; Amenorrhea; Amino Acid Sequence; Anosmia; Applications Grants; Base Sequence; Biochemical; Biological Models; Biological Process; Candidate Disease Gene; Chromosome Mapping; Clinical; Complex; Condition; Constitutional; Coupled; Data; Databases; Defect; Delayed Puberty; Development; Disease; Disease model; Drug or chemical Tissue Distribution; Exposure to; Expressed Sequence Tags; Family; Family Sizes; Follicle Stimulating Hormone; Frequencies; Gene Expression; Gene Mutation; Genes; Genetic Markers; Genetic Predisposition to Disease; Genotype; Goals; Gonadal Steroid Hormones; Gonadal structure; Gonadotropin Hormone Releasing Hormone; Hormones; Human Genome Project; Hypothalamic structure; Immunohistochemistry; In Situ Hybridization; Individual; Infertility; Kallmann Syndrome; Localized; Luteinizing Hormone; Maps; Modification; Mutation; Mutation Spectra; Neurons; Neurosecretory Systems; Northern Blotting; Pathogenesis; Patients; Pattern; Peptide Sequence Determination; Phenotype; Physiological; Physiology; Pituitary Gland; Pituitary Gonadotropins; Population; Precocious Puberty; Process; Production; Proteins; Puberty; RNA; Rare Diseases; Recessive Genes; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smell Perception; Tissues; Transcript; cohort; genetic pedigree; genome wide association study; human disease; in vitro Model; kindred; novel; proband; programs; protein expression; reproductive; response; spatiotemporal; sperm cell

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.

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）是复杂的生殖级联中的第一种激素。 GnRH 由下丘脑释放，刺激垂体分泌黄体生成素 (LH) 和卵泡刺激素 (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 的作用很复杂——它以脉冲式分泌，而不是结构式、时尚式，并且在整个生殖周期中以不同的频率分泌。了解哪些信号调节 GnRH 神经元的发育命运和分泌行为仍然是生殖生物学家的一个主要问题。 该拨款提案将使用 GnRH 分泌有缺陷或缺失的人类疾病模型来解决这个问题。患有特发性低促性腺激素性性腺功能减退症 (IHH) 的患者如果不治疗，将无法进入青春期并且不育。尽管先天性 IHH 是一种罕见疾病，而且家庭规模通常较小，但已发现一个法裔加拿大人后裔的大型近交家庭患有 IHH 和嗅觉丧失症。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。在该提案中，将进一步细化候选区域，开发该区域的完整转录图谱，并利用RT-PCR筛选候选基因的精确基因突变。然后将突变谱与患者的基线临床/生化特征、神经内分泌表型以及对外源性脉动 GnRH 生理替代的反应进行并列，以建立强大的基因型/表型相关性。将研究该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。希望这些信息最终能够用于了解许多由 GnRH 分泌异常定义的人类疾病，包括体质性青春期延迟、下丘脑闭经和中枢性性早熟。