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Disease-associated mutations affect GPR56 protein trafficking and cell surface expression
Zhaohui Jin1, Ian Tietjen, Lihong Bu
1Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Abstract:
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.
Insights
Mutations in the G protein-coupled receptor 56 (GPR56) gene cause Bilateral Frontoparietal Polymicrogyria (BFPP). This study shows how specific GPR56 mutations disrupt protein trafficking, leading to this congenital brain malformation.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Bilateral frontoparietal polymicrogyria (BFPP) is a congenital brain malformation characterized by abnormal cortical surface development.
- BFPP is associated with epilepsy, intellectual disability, and developmental delays.
- Mutations in the G protein-coupled receptor 56 (GPR56) gene are known to cause BFPP, but the underlying molecular mechanisms are not fully understood.
Purpose of the Study:
- To investigate the biochemical properties and protein trafficking of wild-type and mutant GPR56.
- To elucidate how specific GPR56 mutations identified in BFPP patients affect protein function and cellular localization.
Main Methods:
- Analysis of GPR56 protein modifications, including GPS domain cleavage and N-glycosylation.
- Assessment of GPR56 protein trafficking and cell surface expression using various mutant forms.
- Evaluation of the effect of pharmacological chaperones on rescuing mutant GPR56 cell surface expression.
Main Results:
- Wild-type GPR56 undergoes GPS domain cleavage and N-glycosylation, with the N-terminal fragment potentially released from the cell surface.
- Disease-associated mutations in the GPR56 N-terminal domain (R38Q, R38W, Y88C, C91S) impair intracellular trafficking and reduce cell surface expression.
- Mutations in the GPR56 GPS domain (C346S, W349S) severely inhibit protein cleavage and prevent trafficking beyond the endoplasmic reticulum.
- Pharmacological chaperones partially restored cell surface expression of some GPR56 mutants.
Conclusions:
- Specific BFPP-associated mutations in GPR56 disrupt protein trafficking to the plasma membrane.
- Impaired GPR56 trafficking is a key mechanism contributing to the pathogenesis of Bilateral Frontoparietal Polymicrogyria.
- Understanding these molecular defects provides insights into BFPP etiology and potential therapeutic strategies.
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