See Crino (doi:10.1093/brain/awy047) for a scientific commentary on this article. 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.
Bibliographical noteFunding Information:
This work was funded by the Newlife Foundation for Disabled Children (Grant Reference: 11-12/04). This publication is a result of the European Network on Brain Malformations (COST Action CA16118), a network funded by COST (European Cooperation in Science and Technology). The project was also supported by the Wales Epilepsy Research Network and the Wales Gene Park. H.Y. was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development under Award Number R01HD082373; S.F.T. was supported by NIH-NINDS R01NS036654, R01NS065371, and R24NS092989. G.M.M. was supported by NIH-NINDS K08NS092898. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z and Medical Research Council Hub grant G0900747 91070) for the generation of the Sequencing data. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
- N -methyl- d -aspartate receptor