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.

Project Narrative A single patient was previously identified with a neurodegenerative disorder associated with a mutation in the receptor ADGRB2. Recently, a number of other patients with mutations to ADGRB2 have been identified as exhibiting very similar pathology, and thus to test the connection between ADGRB2 variants and this neurological disease we propose to determine whether these newly-identified mutations change receptor function in a manner similar to the earlier case. We furthermore propose to study a novel ligand that we have identified for ADGRB2, with these studies providing insights into potential therapeutic approaches for the treatment of patients harboring pathological ADGRB2 variants.