Functional characterization of a FRMPD4 mutation in a UDP family

UDP 家族中 FRMPD4 突变的功能表征

基本信息

批准号：
8927658
负责人：
TAO WANG
金额：
$ 24.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2014-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927658
关键词：
Adult Affect Amino Acids Behavior Binding Binding Proteins Biological Assay Brain Brain Diseases CDK5 gene Chromosomes, Human, X Clinical Cohort Studies Collaborations Core Facility Correlation Studies Coupling DLG4 gene Defect Dendritic Spines Development Developmental Delay Disorders Disease Dominant-Negative Mutation Epilepsy Etiology Excitatory Synapse Exhibits Exons Family Family member Fragile X Syndrome Gene Family Genes Genetic Genetic Models Genotype Glutamate Receptor Glutamates Goals Health Hereditary Disease Human Impaired cognition In Vitro Intellectual functioning disability Learning Link Memory Metabotropic Glutamate Receptors Missense Mutation Modification Molecular Molecular Genetics Morphogenesis Mus Mutate Mutation N Domain N-Methylaspartate Neurologic Neurons Neurophysiology - biologic function Other Genetics Pathogenesis Patients Phenotype Phosphorylation Polymorphism Analysis Proline-Directed Protein Kinases Protein Binding Domain Proteins Published Comment Receptor Signaling Regulation Reporting Research Personnel Rewards Signal Pathway Signal Transduction Social Interaction Stimulus Symptoms Synapses Synaptic plasticity Techniques Therapeutic Transgenic Mice United States National Institutes of Health Work Writing X-linked intellectual disability abstracting base behavioral response cognitive regression cohort disease-causing mutation embryonic stem cell genetic pedigree homologous recombination human disease insight male meetings metabotropic glutamate receptor type 1 mouse model mutant mouse model nervous system disorder neuromechanism neuronal excitability neurotransmission next generation sequencing novel novel diagnostics proband programs protein function scaffold synaptic function synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Abstract The NIH-undiagnosed disease program (UDP) focuses on defining the molecular basis and mechanisms of rare genetic disorders. A large fraction of patients applying for the UPD program suffer from unknown neurological disorders (43%), which underscores the importance to develop novel diagnostic workup and therapies through close collaborations between clinical and basic investigators. A missense mutation in an X-linked gene, FRMPD4 (also termed Preso1), was recently identified in two male sibs who exhibited global developmental delays, cognitive regression, seizure disorders, and a constellation of other clinical findings. Here, we will examine the hypothesis that human Preso1-K195E is causal for these symptoms. In our previous work, we have identified Preso1 as a co-functional protein with the group 1 metabotropic glutamate receptors (mGluR). Genetic modifications of group 1 mGluR signaling are known to result in various developmental and degenerative phenotypes in mouse models (Niswender and Conn, 2010). Preso1 encodes a multi-domain protein that binds mGluR5 and controls its phosphorylation state, and thereby provides important regulation of mGluR5 function. We propose to utilize in vitro and neuron- based assays, and to generate transgenic mouse models to examine the hypothesis that the K187E mouse mutation of Preso1 results in altered mGluR5 functions that are crucial for synapse formation, synaptic plasticity, and behavioral responses in social interaction and to rewarding stimuli that are important for learning and memory. We will examine convergent mechanisms with other genetic causes of developmental brain disease that impact mGluR5 function including Fragile X Mental Retardation Syndrome. We will also screen for mutations in the Preso gene family members in additional patients with X-linked intellectual disability and/or epilepsy. These studies will determine if Preso1 (K195E) is causal for the neurological defects in the UDP family and if the Preso gene family represents a novel cause for developmental brain disorders. The results will provide mechanistic insights into pathogenesis that will be important for the establishment of rational therapies.

描述（由申请人提供）：摘要 NIH 未确诊疾病计划 (UDP) 重点关注定义罕见遗传性疾病的分子基础和机制。申请 UPD 项目的患者中有很大一部分患有未知的神经系统疾病（43%），这强调了通过临床和基础研究人员之间的密切合作开发新的诊断检查和疗法的重要性。最近在两名男性同胞中发现了 X 连锁基因 FRMPD4（也称为 Preso1）的错义突变，他们表现出整体发育迟缓、认知衰退、癫痫发作和一系列其他临床表现。在这里，我们将检验人类 Preso1-K195E 是这些症状的原因的假设。在我们之前的工作中，我们已经确定 Preso1 是与第 1 组代谢型谷氨酸受体 (mGluR) 的协同功能蛋白。已知 1 组 mGluR 信号传导的基因修饰会导致小鼠模型出现各种发育和退行性表型（Niswender 和 Conn，2010）。 Preso1 编码一种多结构域蛋白，可结合 mGluR5 并控制其磷酸化状态，从而对 mGluR5 功能提供重要调节。我们建议利用体外和基于神经元的测定，并生成转基因小鼠模型来检验这样的假设：Preso1 的 K187E 小鼠突变会导致 mGluR5 功能改变，而 mGluR5 功能对于突触形成、突触可塑性和社交互动中的行为反应至关重要以及奖励对学习和记忆很重要的刺激。我们将研究影响 mGluR5 功能的发育性脑疾病（包括脆性 X 智力迟钝综合症）的其他遗传原因的趋同机制。我们还将在其他 X 连锁智力障碍和/或癫痫患者中筛查 Preso 基因家族成员的突变。这些研究将确定 Preso1 (K195E) 是否是 UDP 家族神经缺陷的原因，以及 Preso 基因家族是否代表发育性脑部疾病的新原因。研究结果将为发病机制提供机制见解，这对于合理疗法的建立非常重要。