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Brain. 2018 Jan 22. doi: 10.1093/brain/awx358. [Epub ahead of print]

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.

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Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK.
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
MRC Computational Genomics Analysis and Training Programme (CGAT), MRC Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Pediatric Neurology Unit, Carmel Medical Center, Haifa, Israel.
Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Department of Neuroradiology, North Bristol NHS Trust, Frenchay Hospital, Bristol BS16 1LE, UK.
Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK.
Genetic Health Queensland, Royal Brisbane and Women's Hospital Campus, Herston, Brisbane, Queensland 4029, Australia.
West Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
Service de Génétique Médicale, Groupe Hospitalier du Havre, Hôpital Jacques Monod, Le Havre, France.
Service de Génétique Médicale, Centre Hospitalier Universitaire de Nice, Nice, France.
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK.
Learning Disabilities Directorate, Abertawe Bro Morgannwg University NHS Trust, Treseder Way, Caerau, Cardiff CF5 5WF, UK.
Clinical Genetics Institute, Kaplan Medical Centre, Rehovot, Israel.
Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Pediatric Neurology Unit, Wolfson Medical Centre, Holon, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Kaiser Permanente Mid-Atlantic States, McLean, VA 22102, USA.
Department of Neurology, Xiangya Hospital, Central South University, Changsha 410013, China.
Department of Neurology, the First Hospital of Shanxi Medical University, Taiyuan, 030001, China.
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98195, USA.
Department of Neurology, University of Washington, Seattle, WA 98195, USA.
Genome and Structural Bioinformatics Group, Institute of Life Science, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
Institute of Human Genetics, University Medical Center Leipzig, Leipzig 04103, Germany.
Imagine Institute, INSERM UMR-1163, Laboratory Genetics and Embryology of Congenital Malformations, Paris Descartes University, Paris, France.
West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.


Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.


GRIN1; GluN1; N-methyl-d-aspartate receptor; NR1; polymicrogyria

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