Establishing the Genetic Etiology for Kallmann Syndrome

建立卡尔曼综合征的遗传病因学

• 批准号: 7218579
• 负责人: Stephanie Beth Seminara
• 金额: $ 36.91万
• 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/7218579
• 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）是复杂生殖级联中的第一激素。GnRH由下丘脑释放，刺激垂体分泌促黄体生成素（LH）和促卵泡激素（FSH）；这些促性腺激素刺激性腺产生性类固醇和卵泡/精子。GnRH的作用是复杂的——它以脉动的方式分泌，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行为仍然是生殖生物学家的一个主要问题。