Biologic Roles of Novel Axonal Guidance Genes in Isolated GnRH Deficiency

新型轴突引导基因在孤立性 GnRH 缺乏症中的生物学作用

基本信息

批准号：
8700856
负责人：
Ravikumar Balasubramanian
金额：
$ 13.7万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-20 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700856
关键词：
Accounting Address Affect Anosmia Axon Biological Biology Boxing CHARGE syndrome Clinical Clinical Investigator Complex Couples Cues Development Developmental Biology Developmental Gene Developmental Process Diagnosis Diagnostic Disease Disease model Dominant-Negative Mutation Embryo Embryonic Development FGF8 gene FGFR1 gene Failure Fertility Funding Genes Genetic Genetic Epistasis Goals Gonadotropin Hormone Releasing Hormone Growth Hereditary Disease Human Human Genetics Hypogonadism Hypothalamic structure Impairment Infertility Investigation Kallmann Syndrome Learning Link Locomotion Measures Mentors Minor Missense Mutation Molecular Molecular Genetics Molecular Mechanisms of Action Mus Mutation National Institute of Child Health and Human Development Neural Crest Neurons Neuropeptides Nose Pathogenesis Patients Penetrance Phenotype Prevalence Study Process Puberty Relative (related person)Reproduction Research Research Priority Research Training Role Secondary to Semaphorin-3A Sexual Maturation Signal Transduction Smell Perception Surface Syndrome Therapeutic Training Travel Tubulin Vision Waardenburg syndrome axonal guidance base beta Tubulin body system career career development cohort design experience gene discovery genetic pedigree hormone deficiency human disease improved insight loss of function loss of function mutation migration neuron development novel olfactory bulb programs public health relevance reproductive reproductive hormone research and development residence sex skills

项目摘要

DESCRIPTION (provided by applicant): Human reproduction is controlled by the pulsatile secretion of the hypothalamic neuropeptide, Gonadotropin-releasing hormone (GnRH), from a network of GnRH neurons. Failure of GnRH neuronal development or its secretion/action results in a rare human genetic disease called isolated GnRH deficiency (IGD). Kallmann Syndrome (KS) represents a distinct neurodevelopmental form of IGD which is characteristically associated with anosmia. To-date, only ~30% of genes linked to KS are currently known. Mutations in two axonal guidance genes, KAL1 and NELF were the first KS-associated genes to be discovered. However, until recently, no similar axonal guidance genes have been implicated in KS. The genetic, molecular and phenotypic characterization of three novel axonal guidance genes forms the basis of this proposal. Five unrelated patients fitting the diagnosis of "Moebius syndrome", a complex neurodevelopmental syndrome, were recently found to harbor a de novo heterozygous missense mutation (p.E410K) affecting the TUBB3 gene, which encodes for an axonal guidance molecule called neuronal ¿-tubulin isotype 3. The PI has now identified that all these patients also display KS, suggesting TUBB3 as a novel KS gene. In addition, mutations in SEMA3A, another axonal guidance molecule and mutations in SOX10, a neural crest migratory gene, were also recently implicated as cause of KS. In Specific Aim #1, the PI will assess the role of these three novel neuro-developmental genes involved in axonal guidance (TUBB3, SEMA3A, and SOX10) in the pathogenesis of IGD by studying the prevalence of mutations, their molecular causal mechanisms and their genetic interactions with other IGD genes. In Specific Aim #2, the reproductive and non-reproductive phenotypes of patients harboring mutations in these three genes will be examined to define their biological role in GnRH neuronal ontogeny and in other organ systems. KS has been thought to represent an aberrant axonal guidance disorder in humans and this proposal will provide confirmatory evidence to this hypothesis. The long term goal of the PI is to become an independently funded clinical investigator and develop a comprehensive research program to study disorders of human reproduction. To achieve his career goals, the PI has assembled a highly dynamic mentoring team to oversee his proposed research. In addition, he has identified key training objectives that will be achieved through practical research experience, coursework and didactic learning. This rigorous career development and research training plan will help him to build on his existing research strengths, acquire new clinical investigatory skills and facilitate his transition to independence.

描述（由申请人提供）：人类生殖是由 GnRH 神经元网络的下丘脑神经肽、促性腺激素释放激素 (GnRH) 的脉冲式分泌控制的。GnRH 神经元发育或其分泌/作用的失败导致了罕见的人类。称为孤立性 GnRH 缺乏症 (IGD) 的遗传病是 IGD 的一种独特的神经发育形式，其特征与此相关。迄今为止，仅约 30% 的与 KS 相关的基因是已知的。两个轴突引导基因 KAL1 和 NELF 是第一个被发现的 KS 相关基因。三个新的轴突引导基因的遗传、分子和表型特征构成了该提议的基础，五名不相关的患者符合“莫比斯综合征”的诊断，这是一种复杂的疾病。神经发育综合征，最近被发现含有影响 TUBB3 基因的从头杂合错义突变 (p.E410K)，该基因编码一种称为神经元 ¿ -微管蛋白同种型 3。PI 现在已确定所有这些患者也表现出 KS，表明 TUBB3 是一种新的 KS 基因。此外，另一种轴突引导分子 SEMA3A 的突变和神经嵴迁移基因 SOX10 的突变也被发现。最近被认为是 KS 的病因。在具体目标 #1 中，PI 将评估这三个参与轴突引导的新型神经发育基因（TUBB3、 SEMA3A 和 SOX10）通过研究突变的发生率、其分子因果机制及其与其他 IGD 基因的遗传相互作用，在特定目标 #2 中，研究了携带这三种突变的患者的生殖和非生殖表型。基因将被检查以确定它们在 GnRH 神经元个体发育和其他器官系统中的生物学作用，KS 被认为代表人类异常的轴突引导障碍，这项提议将为这一假设提供证实的证据。 PI 的长期目标是成为一名独立资助的临床研究者，并开发一个研究人类生殖疾病的综合研究计划。此外，为了实现他的职业目标，PI 还组建了一个充满活力的指导团队来监督他提出的研究。，他确定了通过实践研究经验、课程作业和教学学习将实现的关键培训目标，这一严格的职业发展和研究培训计划将帮助他巩固现有的研究优势，获得新的临床研究技能并促进他的过渡。独立。