Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes

Università di Pisa, Pisa, Tuscany, Italy
Annals of Neurology (Impact Factor: 9.98). 11/2005; 58(5):680-7. DOI: 10.1002/ana.20616
Source: PubMed


Human cerebral cortical polymicrogyria is a heterogeneous disorder, with only one known gene (GPR56) associated with an apparently distinctive phenotype, termed bilateral frontoparietal polymicrogyria (BFPP). To define the range of abnormalities that could be caused by human GPR56 mutations and to establish diagnostic criteria for BFPP, we analyzed the GPR56 gene in a cohort of 29 patients with typical BFPP. We identified homozygous GPR56 mutations in all 29 patients with typical BFPP. The total of 11 GPR56 mutations found represented a variety of distinct founder mutations in various populations throughout the world. In addition, we analyzed five patients with BFPP who did not show GPR56 mutation and found that they define a clinically, radiographically, and genetically distinct syndrome that we termed BFPP2. Finally, we studied seven patients with a variety of other polymicrogyria syndromes including bilateral frontal polymicrogyria, bilateral perisylvian polymicrogyria, and bilateral generalized polymicrogyria. No GPR56 mutation was found in these patients. This study provides a molecular confirmation of the BFPP phenotype and provides the wherewithal for diagnostic screening.

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Available from: William Dobyns, Oct 05, 2014
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    • "GPR56 is one important member of the adhesion GPCR family, as mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP) [6], [7]. Additionally, GPR56 has also been reported to play a critical role in cancer progression by regulating angiogenesis [8], [9]. "
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    ABSTRACT: GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Despite the importance of GPR56 in brain development, where mutations cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP), the signaling mechanism(s) remain largely unknown. Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); however, the biological significance of this cleavage is elusive. Taking advantage of the recent identification of a GPR56 ligand and the presence of BFPP-associated mutations, we investigated the molecular mechanism of GPR56 signaling. We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation. Furthermore, one of the BFPP-associated mutations, L640R, does not affect collagen III-induced lipid raft association of GPR56. Instead, it specifically abolishes collagen III-mediated RhoA activation. Together, these findings reveal a novel signaling mechanism that may apply to other members of the adhesion GPCR family.
    PLoS ONE 06/2014; 9(6):e100043. DOI:10.1371/journal.pone.0100043 · 3.23 Impact Factor
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    • "In humans, there are a total of 33 members of adhesion GPCRs that are thought to mediate cell-cell and cell-extracellular matrix interaction, with GPR56 as the first one linked to a human developmental malformation [1], [2]. Mutations in GPR56 cause BFPP, a specific human brain malformation [3], [4]. To date, a total of fourteen BFPP-associated mutations have been identified, including one deletion, two splicing, and eleven missense mutations [2], [5]. "
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    ABSTRACT: GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain. This domain contains four disease-associated mutations and two N-glycosylation sites. Our study reveals that although glycosylation is not required for ligand binding, each of the four disease-associated mutations completely abolish the ligand binding ability of GPR56. Our data indicates that these four single missense mutations cause BFPP mostly by abolishing the ability of GPR56 to bind to its ligand, collagen III, in addition to affecting GPR56 protein surface expression as previously shown.
    PLoS ONE 01/2012; 7(1):e29818. DOI:10.1371/journal.pone.0029818 · 3.23 Impact Factor
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    • "Bilateral frontal and frontoparietal polymicrogyria (BFPP) have been reported in sporadic patients and in recessive pedigrees (Guerrini et al., 2000; Piao et al., 2005). BFPP has been reported in several consanguineous and nonconsanguineous families and has been associated with mutations of the G protein–coupled receptor gene 6 (GPR56) (Piao et al., 2005). The topography of the cortical abnormality, as well as the pattern of expression of mouse Gpr56, suggest that GPR56 regulates cortical patterning. "

    Epilepsia 02/2010; 51 Suppl 1(s1):10-2. DOI:10.1111/j.1528-1167.2009.02434.x · 4.57 Impact Factor
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