Disease-Associated Mutations and Ligand Activation of the Adhesion G Protein-Coupled Receptor ADGRB2

项目摘要 我们先前发现一名患者表现为痉挛性瘫痪和其他神经症状。 与ADGRB2(也称为“BAI2”)羧基末端区域的功能获得突变有关 或“B2”)，这是一种G蛋白偶联受体，在中枢神经系统中表达最丰富。 最近，临床医生联系了我们，他们发现了更多表现为痉挛的患者。 面瘫和B2的羧基末端区域有突变。我们建议研究这些新的- 识别突变以确定它们是否以类似于 我们早些时候发现的与疾病相关的B2突变。我们还建议研究窝藏在小鼠身上的敲入鼠 这些突变以评估它们是否表现出任何病理，如运动功能紊乱， 可能会模拟在人类患者身上观察到的疾病。此外，我们还建议研究一种潜在的B2配体 我们最近发现的。这个潜在的配体是胎牛血清的一种成分，是被分离出来的 在观察到表达B2的细胞的血清饥饿导致受体显著增加后 表情。鉴于该因子可以下调B2的表达，而激动剂的过度刺激是 G蛋白偶联受体下调的一个众所周知的原因，我们将进行广泛的信号研究 以确定该因子是否真的是B2激动剂。这些研究将有助于揭示生物多样性的基础生物学。 B2还提供了对人类疾病治疗的新途径的见解，包括窝藏 病理性ADGRB2变异以及更广泛的表达野生型B2但患有 来自神经或精神疾病，可能是可以通过调节B2活动来治疗的。

Project Summary We previously identified a patient exhibiting spastic paraparesis and other neurological symptoms associated with a gain-of-function mutation in the carboxyl-terminal region of ADGRB2 (also known as “BAI2” or “B2”), which is a G protein-coupled receptor most abundantly expressed in the central nervous system. Recently, we have been contacted by clinicians who have identified additional patients exhibiting spastic paraparesis and harboring mutations to the carboxyl-terminal region of B2. We propose to study these newly- identified mutations to determine if they alter B2 expression and signaling activity in a manner similar to the disease-associated B2 mutation that we identified earlier. We also propose to study knock-in mice harboring these mutations to assess whether they exhibit any pathology, such as perturbations of motor function, that might model the disease observed in the human patients. Moreover, we propose to study a potential B2 ligand that we have recently identified. This potential ligand is a component of fetal bovine serum and was isolated following observations that serum starvation of cells expressing B2 resulted in a dramatic increase in receptor expression. Given that this factor can down-regulate B2 expression, and that over-stimulation with agonists is a well-known cause of G protein-coupled receptor down-regulation, we will perform extensive signaling studies to determine if this factor is indeed a B2 agonist. These studies will shed light on the fundamental biology of B2 and also provide insights into new avenues of treatment for human disease, including patients harboring pathological ADGRB2 variants as well as the wider population of patients who express wild-type B2 but suffer from neurological or psychiatric disorders that might be treatable via modulation of B2 activity.