Three Mutations in the Bilateral Frontoparietal Polymicrogyria Gene GPR56 in Pakistani Intellectual Disability Families

Abstract

Bilateral frontoparietal polymicrogyria (BFPP, MIM 606854) is a heterogeneous autosomal recessive disorder of abnormal cortical lamination, leading to moderate-to-severe intellectual disability (ID), seizure disorder, and motor difficulties, and caused by mutations in the G protein–coupled receptor 56 (GPR56) gene. Twenty-eight mutations in 40 different families have been reported in the literature. The clinical and neuroimaging phenotype is consistent in these cases. The BFPP cortex consists of numerous small gyral cells, with scalloping of the cortical–white matter junction. There are also associated white matter, brain stem, and cerebellar changes. GPR56 is a member of an adhesion G protein–coupled receptor family with a very long N-terminal stalk and seven transmembrane domains. In this study, we identified three families from Pakistan, ascertained primarily for ID, with overlapping approximately 1 Mb region (chr16:56,973,335–57,942,866) of homozygosity by descent, including 24 RefSeq genes. We found three GPR56 homozygous mutations, using next-generation sequencing. These mutations include a substitutional variant, c.1460T > C; p.L487P, (chr16:57693480 T > C), a 13-bp insertion causing the frameshift and truncating mutation, p.Leu269Hisfs*21 (NM_005682.6:c.803_804insCCATGGAGGTGCT; Chr16: 57689345_57689346insCCATGGAGGTGCT), and a truncating mutation c.1426C > T; p.Arg476* (Chr16:57693446C > T). These mutations fully segregated with ID in these families and were absent in the Exome Aggregation Consortium database that has approximately 8,000 control samples of South Asian origin. Two of these mutations have been reported in ClinVar database, and the third one has not been reported before. Three families from Pakistan with GPR56 mutations have been reported before. With the addition of our findings, the total number of mutations reported in Pakistani patients now is six. These results increase our knowledge regarding the mutational spectrum of the GPR56 gene causing BFPP/ID.

Keywords

G protein-coupled receptor 56 - adhesion G protein-coupled receptor G1 - bilateral frontoparietal polymicrogyria - intellectual disability - next-generation sequencing

• References

• 1 Piao X, Chang BS, Bodell A. , et al. Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol 2005; 58 (05) 680-687
• 2 Chang BS, Piao X, Bodell A. , et al. Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 2003; 53 (05) 596-606
• 3 Bahi-Buisson N, Poirier K, Boddaert N. , et al. GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex. Brain 2010; 133 (11) 3194-3209
• 4 Piao X, Hill RS, Bodell A. , et al. G protein-coupled receptor-dependent development of human frontal cortex. Science 2004; 303 (5666): 2033-2036
• 5 Singer P, Zhang C, Boison D, Yee BK. Dysregulation of brain adenosine is detrimental to the expression of conditioned freezing but not general Pavlovian learning. Pharmacol Biochem Behav 2013; 104: 80-89
• 6 Harbord MG, Boyd S, Hall-Craggs MA, Kendall B, McShane MA, Baraitser M. Ataxia, developmental delay and an extensive neuronal migration abnormality in 2 siblings. Neuropediatrics 1990; 21 (04) 218-221
• 7 Parrini E, Ferrari AR, Dorn T, Walsh CA, Guerrini R. Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations. Epilepsia 2009; 50 (06) 1344-1353
• 8 Luo R, Jeong SJ, Jin Z, Strokes N, Li S, Piao X. G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination. Proc Natl Acad Sci U S A 2011; 108 (31) 12925-12930
• 9 Quattrocchi CC, Zanni G, Napolitano A. , et al. Conventional magnetic resonance imaging and diffusion tensor imaging studies in children with novel GPR56 mutations: further delineation of a cobblestone-like phenotype. Neurogenetics 2013; 14 (01) 77-83
• 10 Fujii Y, Ishikawa N, Kobayashi Y, Kobayashi M, Kato M. Compound heterozygosity in GPR56 with bilateral frontoparietal polymicrogyria. Brain Dev 2014; 36 (06) 528-531
• 11 Santos-Silva R, Passas A, Rocha C. , et al. Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype. Neuropediatrics 2015; 46 (02) 134-138
• 12 Desai NA, Udani V. GPR56-related polymicrogyria: clinicoradiologic profile of 4 patients. J Child Neurol 2015; 30 (13) 1819-1823
• 13 Chiang NY, Hsiao CC, Huang YS. , et al. Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. J Biol Chem 2011; 286 (16) 14215-14225
• 14 Bockaert J, Perroy J, Bécamel C, Marin P, Fagni L. GPCR interacting proteins (GIPs) in the nervous system: roles in physiology and pathologies. Annu Rev Pharmacol Toxicol 2010; 50: 89-109
• 15 Druey KM. Regulation of G-protein-coupled signaling pathways in allergic inflammation. Immunol Res 2009; 43 (1–3): 62-76
• 16 Seelow D, Schuelke M, Hildebrandt F, Nürnberg P. HomozygosityMapper--an interactive approach to homozygosity mapping. Nucleic Acids Res 2009; 37 (Web Server issue): W593-W599
• 17 Harripaul R, Vasli N, Mikhailov A. , et al. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol Psychiatry 2018; 23 (04) 973-984
• 18 McKenna A, Hanna M, Banks E. , et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010; 20 (09) 1297-1303
• 19 Yang H, Wang K. Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protoc 2015; 10 (10) 1556-1566
• 20 Landrum MJ, Lee JM, Benson M. , et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 2016; 44 (D1): D862-D868