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Author Notes:

Corresponding author: rhall3@emory.edu, Telephone: 404-727-3699, Fax: 404-727-0365.

The authors are grateful to Drs. Kelly Monk, Jennifer Mulle, Ayush Kishore, Sharon Owino, Michelle Giddens and Brilee Coleman for helpful discussions, and to Drs. John Hepler, Hannah Stoveken, and Gregory Tall for advice on G protein pathways.

The authors have no conflicts of interest to declare.


Research Funding:

This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, Office of the Director, National Institutes of Health (NIH). Additional funding provided by NIH NINDS R21 NS094136


  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • activation
  • brain
  • Gz
  • G beta gamma
  • NFAT
  • RGS20
  • SITE

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


Journal Title:

Human Mutation


Volume 38, Number 12


, Pages 1751-1760

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2017 Wiley Periodicals, Inc.

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