De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Fry Andrew E, Fawcett Katherine A, Zelnik Nathanel, Yuan Hongjie, Thompson Belinda A N, Shemer-Meiri Lilach, Cushion Thomas D, Mugalaasi Hood, Sims David, Stoodley Neil, Chung Seo-Kyung, Rees Mark I, Patel Chirag V, Brueton Louise A, Layet Valérie, Giuliano Fabienne, Kerr Michael P, Banne Ehud, Meiner Vardiella, Lerman-Sagie Tally, Helbig Katherine L, Kofman Laura H, Knight Kristin M, Chen Wenjuan, Kannan Varun, Hu Chun, Kusumoto Hirofumi, Zhang Jin, Swanger Sharon A, Shaulsky Gil H, Mirzaa Ghayda M, Muir Alison M, Mefford Heather C, Dobyns William B, Mackenzie Amanda B, Mullins Jonathan G L, Lemke Johannes R, Bahi-Buisson Nadia, Traynelis Stephen F, Iago Heledd F, Pilz Daniela T
Аннотация
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.