The Genetics of Joubert Syndrome

朱伯特综合征的遗传学

基本信息

批准号：
7385956
负责人：
RUSSELL JAMES FERLAND
金额：
$ 13.38万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-19 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7385956
关键词：
Adaptor Signaling Protein Affect Alleles Animal Model Autistic Disorder Behavior Biological Brain Brain Stem Breathing Candidate Disease Gene Cell Line Cell Nucleus Cerebellar vermis structure Chromosome Mapping Chromosomes Clinical Co-Immunoprecipitations Code Cognitive Coiled-Coil Domain Condition Congenital cerebellar hypoplasia Data Defect Development Developmental Brain Malformation Developmental Delay Disorders Diagnosis Disease Doctor of Philosophy Epilepsy Exons Eye Movements Family Functional disorder Gene Expression Genes Genetic Genetic Heterogeneity Genomics Goals Hippocampus (Brain)Human Hypothalamic structure Immunohistochemistry In Situ Hybridization Individual Intention Joubert syndrome Lead Maps Medical Societies Mental Retardation Mentors Messenger RNA Methods Molecular Molecular Genetics Mus Muscle hypotonia Mutation Neonatal Neuroanatomy Neurosciences Northern Blotting Patients Personal Satisfaction Play Population Process Proteins RNA Splicing RNA analysis Range Recruitment Activity Research Research Proposals Rett Syndrome Reverse Transcriptase Polymerase Chain Reaction Role SH3 Domains Sequence Analysis Signal Pathway Structure Syndrome Testing Therapeutic Training Work Yeasts axonal pathfinding career gene function genetic analysis genetic pedigree immortalized cell insight interest malformation neurogenesis neurogenetics neuropathology novel protein protein interaction psychologic respiratory yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Developmental malformations of the brain are collectively recognized as an increasingly important cause of mental retardation, epilepsy, and perhaps autism. These disorders have deleterious effects on both the psychological and physical well-being of the affected individual. However, identification of causative genes and elucidation of their functions in the context of these developmental brain abnormalities provide valuable insights into human brain development. Joubert syndrome (JS) is an autosomal recessive developmental brain condition, which is characterized anatomically by cerebellar and brainstem malformations, and clinically by hypotonia, breathing abnormalities, atypical eye movements, cognitive problems, and autistic features. The goals of this proposal are to identify one of the causative genes for JS and to study the function of this gene in brain development. Our preliminary work mapped a JS locus to chromosome 6q. Our further studies identified a causative gene for JS, which is a novel gene encoding a putative adaptor protein called AHI1. Specific Aim 1 will test the hypothesis that AHI1 is a causative gene for JS by further analyzing the genetic and clinical aspects of JS in our patients, performing mutational analyses of AHI1 in our JS families, and analyzing the genomic structure of AHI1. Specific Aim 2 will characterize the temporal and spatial expression of AHI1 at both the mRNA and protein levels in addition to generating and characterizing mice with a targeted deletion of Ahi1. Specific Aim 3 will identify proteins that interact with AHI1 by yeast two-hybrid and confirm these interactions by co-immunoprecipitation analyses. The applicant has a PhD. He earned his doctoral degree in Neuroscience studying the role of the perirhinal cortex, the ventromedial nucleus of the hypothalamus, and hippocampal neurogenesis in animal models of epilepsy. His mentor is Christopher A. Walsh, MD, PhD, whose research interests center on genetic approaches toward understanding basic mechanisms governing the development of the brain. This research proposal focuses on training the candidate in methods of 1) genetic mapping, linkage analysis, and genetic analyses, and 2) neurogenetics and molecular biological approaches to brain development. It is the candidate's intention to combine both his previous training in neuroanatomy and behavior with these new molecular and genetic approaches in order to pursue an academic career in Neuroscience.

描述（由申请人提供）：大脑的发育畸形统一被认为是越来越重要的智力，癫痫和自闭症的重要原因。这些疾病对受影响的个体的心理和身体健康都有有害影响。但是，在这些发育脑部异常的背景下，鉴定病因基因并阐明其功能，为人脑发育提供了宝贵的见解。乔伯特综合征（JS）是一种常染色体隐性发育性脑部疾病，在小脑和脑干畸形上的解剖学表征，在临床上通过低血压，呼吸异常，非典型眼动运动，认知问题和自闭症特征。该提案的目标是确定JS的病因基因之一，并研究该基因在大脑发育中的功能。我们的初步工作将JS基因座映射到6Q染色体。我们的进一步研究确定了JS的病因基因，该基因是一种编码称为AHI1的推定衔接蛋白的新型基因。具体目标1将通过进一步分析患者JS的遗传和临床方面，在我们的JS家族中对AHI1进行突变分析并分析AHI1的基因组结构，从而检验AHI1是JS的病因基因。特定的目标2将表征AHI1在mRNA和蛋白质水平上的时间和空间表达，除了用靶向aHi1的靶向缺失产生和表征小鼠。特定目标3将鉴定通过酵母两杂交与AHI1相互作用的蛋白质，并通过共免疫沉淀分析确认这些相互作用。申请人有博士学位。他在神经科学方面获得了博士学位，研究了癫痫动物模型中的下丘脑皮层，下丘脑的腹侧核以及海马神经发生的作用。他的导师是医学博士的克里斯托弗·沃尔什（Christopher A.这项研究提案的重点是培训候选者的方法1）遗传学映射，链接分析和遗传分析以及2）神经遗传学和分子生物学方法用于脑发育。候选人的意图是将他以前的神经解剖学和行为培训与这些新的分子和遗传方法相结合，以从事神经科学的学术生涯。