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Hum Mutat. 2017 Dec;38(12):1751-1760. doi: 10.1002/humu.23336. Epub 2017 Sep 20.

A disease-associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity.

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Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia.
NIH Undiagnosed Diseases Program, Office of the Director, NIH, Bethesda, Maryland.


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 Gαz , with the R1465W mutation conferring increased coupling to Gαi . 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.


Gz; Gβγ; NFAT; RGS20; activation; brain

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