GPR37L1 mutation associated with a novel neurological disorder

GPR37L1 突变与新型神经系统疾病相关

• 批准号: 8871619
• 负责人: Randy A. Hall
• 金额: $ 19.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8871619
• 关键词: Affect; Agonist; Alleles; Amino Acids; Asparagine; Astrocytes; Biological Assay; Biology; Calcium; Cell membrane; Cessation of life; Child; Coupled; Coupling; Cyclic AMP; Disease; Environment; Evolution; Exhibits; Exons; Family; Family member; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Mutation; Generations; Genes; Genetic study; Headache; Hereditary Disease; Human; Inborn Genetic Diseases; Induced Mutation; Inherited; Knock-out; Knockout Mice; Laboratories; Light; Lysine; Mediating; Membrane Protein Traffic; Missense Mutation; Mus; Mutate; Mutation; Nerve Degeneration; Neuraxis; Neurons; Oligodendroglia; Oxidative Stress; Parents; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Production; Property; Proteins; Puberty; Reagent; Regulation; Relative (related person); Role; Seizures; Signal Transduction; Single Nucleotide Polymorphism; Solid; Staging; Stroke; Teenagers; Testing; Toxic effect; Transfection; Ubiquitination; Untranslated RNA; Variant; consanguineous family; cytotoxic; exome; gain of function; human disease; in vivo; insight; nervous system disorder; neuropathology; novel; protein folding; protein function; public health relevance; receptor; rho; trafficking

 DESCRIPTION (provided by applicant): GPR37L1 is a G protein-coupled receptor that is expressed almost exclusively in the central nervous system. This receptor is highly expressed in astrocytes as well as in oligodendrocytes and certain neuronal populations, and my laboratory recently identified GPR37L1 as a receptor for the secreted neuroprotective and glioprotective factor prosaposin. A GPR37L1 mutation was recently found to be associated with a novel inherited neurological disorder characterized by headaches and seizures starting at the onset of puberty, with the seizures growing more frequent and severe throughout the teen years and ultimately resulting in death by the late teens. The GPR37L1 mutation identified in the affected members of this family is a missense mutation that changes an amino acid in the receptor's third cytoplasmic loop, a region of most G protein-coupled receptors that is important for controlling their signaling and regulation. We will assess the effects of the mutation on the folding, trafficking and signaling of GPR37L1 in order to determine how this mutation might be causing human disease and how patients harboring this mutation might be treated. In addition to providing insights into the neurological disorder associated with the GPR37L1 mutation, these studies will also shed significant light on the normal function of GPR37L1 and thereby set the stage for targeting this receptor pharmacologically in order to generally benefit patients sufferin from stroke and/or other neurodegenerative conditions.

 描述（由申请人提供）：GPR37L1是一种G蛋白偶联受体，几乎仅在中枢神经系统中表达。这种受体在星形胶质细胞、少突胶质细胞和某些神经元群中高度表达，我的实验室最近发现 GPR37L1 是分泌的神经保护和神经胶质保护因子 prosaposin 的受体。最近发现 GPR37L1 突变与一种新型遗传性神经系统疾病有关，其特征是从青春期开始出现头痛和癫痫发作，癫痫发作在整个青少年时期变得更加频繁和严重，最终导致青少年死亡。在该家族受影响成员中发现的 GPR37L1 突变是一种错义突变，它改变了受体第三细胞质环中的氨基酸，该区域是大多数 G 蛋白偶联受体的区域，对于控制其信号传导和调节非常重要。我们将评估该突变对 GPR37L1 折叠、运输和信号传导的影响，以确定该突变如何导致人类疾病以及如何治疗携带该突变的患者。除了深入了解与 GPR37L1 突变相关的神经系统疾病外，这些研究还将揭示 GPR37L1 的正常功能，从而为药理学靶向该受体奠定基础，从而普遍造福患有中风和/或其他神经退行性疾病的患者。