De novo mutations in GRIN1 cause extensive bilateral polymicrogyria

AbstractSee 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 foundde novo heterozygous missenseGRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine furtherde novo missenseGRIN1 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 theN-methyl-d-aspartate receptor. The polymicrogyria-associatedGRIN1 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 inGRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associatedGRIN1 mutations significantly alter thein 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 previousGRIN1 mutations have generally caused loss of function, and becauseN-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand th...

Source: Brain - January 22, 2018 Category: Neurology Source Type: research