biostudies-literaturePurcell RHNational Institute of Neurological Disorders and StrokeNIH Office of the DirectorNINDS NIH HHSNational Human Genome Research Institute1751-1760https://www.ebi.ac.uk/biostudies/studies/S-EPMC5679302biostudies-literatureUnknown38(12)Mutations in G protein-coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C-terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N-terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild-type BAI2 primarily couples to Gα_z , with the R1465W mutation conferring increased coupling to Gα_i . The R1465W mutation also increases the total and surface expression of BAI2. The mutation has no effect on receptor binding to β-arrestins, but does perturb binding to the endocytic protein endophilin A1, identified here as a novel interacting partner for BAI2. These studies provide new insights into the signaling capabilities of the adhesion GPCR BAI2/ADGRB2 and shed light on how an apparent gain-of-function mutation to the receptor's C-terminus may lead to human disease.Human mutationA disease-associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity.PMC5679302T32 NS096050R21 NS094136).R21 NS094136Purcell RHToro CGahl WAHall RAfalseA disease-associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity.Mutations in G protein-coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C-terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N-terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild-type BAI2 primarily couples to Gα_z , with the R1465W mutation conferring increased coupling to Gα_i . The R1465W mutation also increases the total and surface expression of BAI2. The mutation has no effect on receptor binding to β-arrestins, but does perturb binding to the endocytic protein endophilin A1, identified here as a novel interacting partner for BAI2. These studies provide new insights into the signaling capabilities of the adhesion GPCR BAI2/ADGRB2 and shed light on how an apparent gain-of-function mutation to the receptor's C-terminus may lead to human disease.2017-01-01T00:00:00Z2017 Dec2025-04-22T09:11:05.395Z2019-03-27T00:09:08ZS-EPMC56793022889123610.1002/humu.23336