Functional dissection of a novel causative gene for Kallmann syndrome

卡尔曼综合征新致病基因的功能解析

基本信息

批准号：
10583057
负责人：
Xiaoyan Zheng
金额：
$ 16.15万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-12 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583057
关键词：
Accounting Anosmia Area Axon BMP4 Biological Availability Biological Models Clinical Delayed Puberty Dental Development Diagnosis Digit structure Disease Dissection Drosophila genus Exhibits Face Family member Female GNRH1 gene Genes Genetic Genetic Counseling Genetic Diseases Genetic Heterogeneity Gonadotropin Hormone Releasing Hormone Growth Homologous Gene Hypothalamic structure Impairment Infertility Investigation Kallmann Syndrome Kidney Klinefelter&apos s Syndrome Ligands Mammalian Cell Manuals Mendelian disorder Molecular Mutation Nervous System Neurons Olfactory Nerve Pathogenicity Patients Pattern Persons Phenotype Protein Family Puberty Regulation Research Role Signal Pathway Signal Transduction Smell Perception Structure Susceptibility Gene Synkinesis Variant Wing Work autosome bone morphogenetic protein receptors causal variant exome sequencing extracellular hearing impairment hyposmia imaginal disc insight loss of function mutation male migration neurotrophic factor novel olfactory bulb permissiveness protein function psychologic receptor binding

项目摘要

Project Summary/Abstract Kallmann syndrome (KS) is a condition characterized by delayed or absent puberty and an impaired sense of smell. KS results from the deficiency of early development and migration of GnRH-synthesizing neurons and olfactory nerves. Besides anosmia, there are several other associated non-reproductive features, including midline facial, dental, and digit anomalies, hearing impairment, bimanual synkinesis, and renal abnormalities. KS is clinically and genetically heterogeneous and not strictly a monogenic Mendelian disease. There are >25 different causal genes, each accounting for less than 10% of KS cases, that have been identified to date, yet the genetic basis of the vast majority of KS cases remains unknown. The KS-associated genes either act alone (monogenic) or in combination (oligogenic). However, the molecular mechanisms that modulate the oligogenic interactions are far from being elucidated since the exact roles of some susceptibility genes in the regulation of the GnRH/ olfactory nervous system are yet to be discovered. Therefore, molecular characterization of newly identified KS causative genes and their associated signaling pathways is crucial for fully determining the genetic cause of KS. The current proposal aims to understand how Neuron-Derived Neurotrophic Factor (NDNF), a novel causative gene for KS, modulates BMP signaling. If successful, the results will provide mechanistic insight underlying KS, inform genetic counseling of KS, and, in the long run, contribute to a timely diagnosis and treatment to minimize physical and psychological effects on KS patients.

项目摘要/摘要 Kallmann综合征（KS）是一种疾病，其特征是延迟或缺乏青春期的疾病闻。 KS是由于早期发展和GNRH合成神经元和嗅觉神经。除厌食外，还有其他几个相关的非复制功能，包括中线面部，牙齿和数字异常，听力障碍，双人合子和肾脏异常。 KS在临床和遗传上是异质的，而不是严格的单基因孟德尔氏病。有> 25 迄今已确定的不同因果基因，每个因果基因占KS病例的10％，但绝大多数KS病例的遗传基础仍然未知。 KS相关基因要么单独起作用（单基因）或组合（寡聚）。但是，调节寡原性的分子机制由于某些敏感性基因在调节中的确切作用，因此相互作用远非阐明 GNRH/嗅觉神经系统尚未发现。因此，新近的分子表征确定的KS致病基因及其相关的信号通路对于完全确定遗传至关重要 KS的原因。当前的建议旨在了解神经元衍生的神经营养因子（NDNF）是一种新颖的病因 KS的基因调节BMP信号传导。如果成功，结果将为KS提供机械洞察力，向KS的遗传咨询提供信息，从长远来看，会及时诊断和治疗最大程度地减少对KS患者的身体和心理影响。