期刊
BRAIN
卷 141, 期 -, 页码 698-712出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awx358
关键词
polymicrogyria; GRIN1; GluN1; NR1; N-methyl-d-aspartate receptor
资金
- Newlife Foundation for Disabled Children [11-12/04]
- COST (European Cooperation in Science and Technology)
- Wales Epilepsy Research Network
- Wales Gene Park
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD082373]
- NIH-NINDS [R01NS036654, R01NS065371, R24NS092989, K08NS092898]
- Wellcome Trust [090532/Z/09/Z]
- Medical Research Council Hub [G0900747 91070]
- MRC [MC_PC_15065] Funding Source: UKRI
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD083091, R01HD082373] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS065371, R24NS092989, K08NS092898, R01NS069605, R01NS092772, R01NS036654] Funding Source: NIH RePORTER
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据