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

> **NIH NIH R21** · EMORY UNIVERSITY · 2023 · $430,375

## Abstract

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.

## Key facts

- **NIH application ID:** 10811019
- **Project number:** 1R21NS133638-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Randy A. Hall
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $430,375
- **Award type:** 1
- **Project period:** 2023-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811019

## Citation

> US National Institutes of Health, RePORTER application 10811019, Disease-Associated Mutations and Ligand Activation of the Adhesion G Protein-Coupled Receptor ADGRB2 (1R21NS133638-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10811019. Licensed CC0.

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