GPR37L1 mutation associated with a novel neurological disorder

 描述（由申请人提供）：GPR 37 L1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以及少突胶质细胞和某些神经元群体中高度表达，我的实验室最近鉴定出GPR 37 L1作为分泌的神经保护和胶质保护因子saposin的受体。最近发现GPR 37 L1突变与一种新的遗传性神经系统疾病有关，其特征是从青春期开始的头痛和癫痫发作，在整个青少年时期癫痫发作越来越频繁和严重，最终导致青少年晚期死亡。在该家族的受影响成员中鉴定的GPR 37 L1突变是一种错义突变，其改变了受体第三胞质环中的氨基酸，该区域是大多数G蛋白偶联受体的一个区域，对于控制其信号传导和调节非常重要。我们将评估突变对GPR 37 L1折叠、运输和信号传导的影响，以确定这种突变如何导致人类疾病以及如何治疗携带这种突变的患者。除了提供与GPR 37 L1突变相关的神经系统疾病的见解外，这些研究还将揭示GPR 37 L1的正常功能，从而为靶向这种受体的研究奠定基础，以便使患有中风和/或其他神经退行性疾病的患者普遍受益。

 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.