Human Molecular Genetics Advance Access originally published online on June 18, 2007
Human Molecular Genetics 2007 16(16):1972-1985; doi:10.1093/hmg/ddm144
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Disease-associated mutations affect GPR56 protein trafficking and cell surface expression
1 Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School and 2 Department of Neurology, Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
* To whom correspondence should be addressed at: Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Tel: +1 6179192357; Fax: +1 6177300260; Email: xianhua.piao{at}childrens.harvard.edu/
Received April 11, 2007; Revised June 3, 2007; Accepted June 3, 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, whereas the two mutations in the GPS domain (C346S and W349S) produce proteins with dramatically impaired cleavage that fail to traffic beyond the endoplasmic reticulum. 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 providing insights into how BFPP-associated mutations affect GPR56 function.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Walsh, D. Whelan, A. Bielanowicz, B. Skinner, R. J. Aitken, M. K. O'Bryan, and B. Nixon Identification of the Molecular Chaperone, Heat Shock Protein 1 (Chaperonin 10), in the Reproductive Tract and in Capacitating Spermatozoa in the Male Mouse Biol Reprod, June 1, 2008; 78(6): 983 - 993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Li, Z. Jin, S. Koirala, L. Bu, L. Xu, R. O. Hynes, C. A. Walsh, G. Corfas, and X. Piao GPR56 Regulates Pial Basement Membrane Integrity and Cortical Lamination J. Neurosci., May 28, 2008; 28(22): 5817 - 5826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Iguchi, K. Sakata, K. Yoshizaki, K. Tago, N. Mizuno, and H. Itoh Orphan G Protein-coupled Receptor GPR56 Regulates Neural Progenitor Cell Migration via a G{alpha}12/13 and Rho Pathway J. Biol. Chem., May 23, 2008; 283(21): 14469 - 14478. [Abstract] [Full Text] [PDF]
|
|