Disease-associated GPR56 Mutations Cause Bilateral Frontoparietal Polymicrogyria via Multiple Mechanisms

Abstract

Loss-of-function mutations in the gene encoding G proteincoupled receptor 56 (GPR56) lead to bilateral frontoparietal polymicrogyria (BFPP), an autosomal recessive disorder affecting brain development. The GPR56 receptor is a member of the adhesion-GPCR family characterized by the chimeric composition of a long ectodomain (ECD), a GPCR proteolysis site (GPS), and a sevenpass transmembrane (7TM) moiety. Interestingly, all identified BFPP-associated missense mutations are located within the extracellular region of GPR56 including the ECD, GPS, and the extracellular loops of 7TM. In the present study, a detailed molecular and functional analysis of the wild-type GPR56 and BFPP-associated point mutants shows that individual GPR56 mutants most likely cause BFPP via different combination of multiple mechanisms. These include reduced surface receptor expression, loss of GPS proteolysis, reduced receptor shedding, inability to interact with a novel protein ligand, and differential distribution of the 7TM moiety in lipid rafts. These results provide novel insights into the cellular functions of GPR56 receptor and reveal molecular mechanisms whereby GPR56 mutations induce BFPP.

Shear Stress–Dependent Downregulation of the Adhesion-G Protein–Coupled Receptor CD97 on Circulating Leukocytes upon Contact with Its Ligand CD55

“…Similar characteristics have been reported for GPR56, an aGPCR expressed by neurons, various malignant cells, and cytotoxic lymphocytes (2,44). GPR56 binds different ligands in man and mouse, including tissue transglutaminase 2 and collagen III (14,19,45). Defective expression of GPR56 on neurons disturbs the integrity of the pial basement membrane and the migration of developing neurons, resulting in a severe human brain malformation called bilateral frontoparietal polymicrogyria (46,47).…”

Heparin interacts with the adhesion GPCR GPR56, reduces receptor shedding, and promotes cell adhesion and motility

“…In brain development, the GPR56-collagen-III interaction is crucial for the integrity of the pial basement membrane and proper cerebral cortex lamination (Luo et al, 2011). In a previous report, we have described a new cellular protein ligand that interacts with the NTF of wild-type GPR56 but not with BFPP-associated point mutants (Chiang et al, 2011). In addition to the aforementioned ligands, which presumably interact with GPR56 in trans, examples of cis-acting binding partners have also been noted.…”

“…Shedding is likely to generate distinct soluble receptor fragments that have different cellular functions from the membrane-bound proteins. Previously, we and others have detected the presence of soluble GPR56 (sGPR56; the NTF that has been shed from the membrane) in transfected cells, suggesting constitutive GPR56 shedding (Chiang et al, 2011;Jin et al, 2007;Yang et al, 2015). More intriguingly, expression of a truncated GPR56 receptor that lacked the NTF was shown to signal constitutively (Paavola et al, 2011).…”

Vigabatrin efficacy in GPR56‐associated polymicrogyria: The role of GABAA receptor pathway

“…1,2 The main clinical features of BFPP include severe mental retardation, developmental delay, and epilepsy, often presenting as Lennox-Gastaut syndrome. 3 Although there is some evidence of the pathogenesis of BFPP, 4 the pathophysiology of the resulting epilepsy is poorly understood. Localized freezing in neonatal mice brain is currently used as an experimental model mimicking the histologic characteristics of a human four-layered polymicrogyria.…”

“…However, the literature also notes that serious adverse reactions are rare, especially those leading to fatalities. 3,4 One patient with hyperammonemia was observed with secondary symptoms (nausea, vomiting, lack of appetite, fatigue, drowsiness, confusion, cognitive slowing, or loss of consciousness). It is not mentioned if this was in the control or intervention group.…”