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De novo mutations in GRIN1 cause extensive bilateral polymicrogyria
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837214/ https://www.ncbi.nlm.nih.gov/pubmed/29365063 http://dx.doi.org/10.1093/brain/awx358 |
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author | 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 |
author_facet | 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 |
author_sort | Fry, Andrew E |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5837214 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58372142018-03-09 De novo mutations in GRIN1 cause extensive bilateral polymicrogyria 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 Brain Original Articles 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. Oxford University Press 2018-03 2018-01-22 /pmc/articles/PMC5837214/ /pubmed/29365063 http://dx.doi.org/10.1093/brain/awx358 Text en © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles 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 De novo mutations in GRIN1 cause extensive bilateral polymicrogyria |
title |
De novo mutations in GRIN1 cause extensive bilateral polymicrogyria |
title_full |
De novo mutations in GRIN1 cause extensive bilateral polymicrogyria |
title_fullStr |
De novo mutations in GRIN1 cause extensive bilateral polymicrogyria |
title_full_unstemmed |
De novo mutations in GRIN1 cause extensive bilateral polymicrogyria |
title_short |
De novo mutations in GRIN1 cause extensive bilateral polymicrogyria |
title_sort | de novo mutations in grin1 cause extensive bilateral polymicrogyria |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837214/ https://www.ncbi.nlm.nih.gov/pubmed/29365063 http://dx.doi.org/10.1093/brain/awx358 |
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