De novo mutations in GRIN1 cause extensive bilateral polymicrogyria

Andrew Fry, Katherine Fawcett, Nathanel Zelnik, Hongjie Yuan, Belinda Thomposon, Lilach Shemer-Meiri, thomas cushion, Hood Mugalaasi, David Sims, Neil Stoodley, Seo-Kyung Chung, Mark I. Rees, Chirag V. Patel, Louise A. Brueton, Valerie Layet, Fabienne Giuliano, Michael P. Kerr, Ehud Banne, Vardiella Meiner, Tally Lerman-SagieKatherine L. Helbig, Laura H. Kofman, Kristin M. Knight, Wenjuan Chen, Varun Kannan, Chun Hu, Hirofumi Kusumoto, Jin Zhang, Sharon A. Swanger, Gil H. Shaulsky, Ghayda M. Mirzaa, Alison M. Muir, Heather C. Mefford, William B. Dobyns, Amanda Mackenzie, Jonathan G. L. Mullins, Johannes R. Lemke, Nadia Bahi-Buisson, Stephen f. Traynelis, Heledd F. Iago, Daniela T. Pilz

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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.

Original languageEnglish
Pages (from-to)698-712
Number of pages15
JournalBrain : A Journal of Neurology
Issue number3
Early online date22 Jan 2018
Publication statusPublished - 31 Mar 2018

Bibliographical note

© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.


  • GRIN1
  • GluN1
  • N -methyl- d -aspartate receptor
  • NR1
  • Polymicrogyria

ASJC Scopus subject areas

  • Clinical Neurology


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