Human Molecular Genetics Advance Access published online on June 18, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm146
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Protective Effect of Complement Factor B and Complement Component 2 Variants in Age-related Macular Degeneration
1 Center for Human Genetics Research, Vanderbilt University, Nashville, TN USA 2 Center for Human Genetics, Duke University, Durham, NC USA 3 Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN USA 4 Duke University Eye Center and Department of Ophthalmology, Duke University Medical Center, Durham, NC USA 5 Institute for Human Genomics, University of Miami, Miami, FL USA
* Corresponding Author: Jonathan L. Haines, Ph.D., Ph: (615) 343-5851, Fax: (615) 343-8619 Email: Jonathan{at}chgr.mc.vanderbilt.edu
Received April 16, 2007; Revised May 1, 2007; Accepted May 1, 2007
Bilateral frontoparietal polymicrogyria (BFPP) is a congenital brain malformation resulting in irregularities on the surface of the cortex where normally convoluted gyri are replaced by numerous (poly) and noticeably smaller (micro) gyri. Individuals with BFPP suffer from epilepsy, mental retardation, language impairment and motor developmental delay. Mutations in the gene encoding G protein coupled receptor 56 (GPR56) cause BFPP; however, it remains unclear how these mutations affect GPR56 function. Here, we examine the biochemical properties and protein trafficking of wild type and mutant GPR56. We demonstrate that GPR56 protein undergoes two major modifications, GPS domain-mediated protein cleavage and N-glycosylation, and that the N-terminal fragment can be released from the cell surface. In contrast to the wild type protein, disease-associated GPR56 missense mutations in the tip of the N-terminal domain (R38Q, R38W, Y88C, and C91S) produce proteins with reduced intracellular trafficking and poor cell surface expression, while the two mutations in the GPS domain (C346S and W349S) produce proteins with dramatically impaired cleavage that fail to traffic beyond the ER. Cell trafficking impairments are abrogated in part by pharmacological chaperones that can partially rescue mutant GPR56 cell surface expression. These data demonstrate that some BFPP-associated mutations in GPR56 impair trafficking of the mutant protein to the plasma membrane, thus provide insights into how BFPP-associated mutations affect GPR56 function.
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