De novo mutations in GRIN1 cause extensive bilateral polymicrogyria

Andrew Fry, Katherine Fawcett, Nathanel Zelnik, Hongjie Yuan, Belinda Thomposon, Lilach Shemer-Meiri, thomas cushion, Hood Mugalaasi, David Sims, Neil Stoodley, Seo-Kyung Chung, Mark I. Rees, Chirag V. Patel, Louise A. Brueton, Valerie Layet, Fabienne Giuliano, Michael P. Kerr, Ehud Banne, Vardiella Meiner, Tally Lerman-SagieKatherine L. Helbig, Laura H. Kofman, Kristin M. Knight, Wenjuan Chen, Varun Kannan, Chun Hu, Hirofumi Kusumoto, Jin Zhang, Sharon A. Swanger, Gil H. Shaulsky, Ghayda M. Mirzaa, Alison M. Muir, Heather C. Mefford, William B. Dobyns, Amanda Mackenzie, Jonathan G. L. Mullins, Johannes R. Lemke, Nadia Bahi-Buisson, Stephen f. Traynelis, Heledd F. Iago, Daniela T. Pilz

Research output: Contribution to journalArticle

14 Citations (Scopus)
15 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)698-712
Number of pages15
JournalBrain : A Journal of Neurology
Volume141
Issue number3
Early online date22 Jan 2018
DOIs
Publication statusPublished - 31 Mar 2018

Fingerprint

Mutation
N-Methyl-D-Aspartate Receptors
Missense Mutation
Exome
Polymicrogyria
Malformations of Cortical Development
Microcephaly
Vision Disorders
Protons
Electrodes
Animal Models
Ligands
Population

Keywords

  • GRIN1
  • GluN1
  • N -methyl- d -aspartate receptor
  • NR1
  • Polymicrogyria

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Fry, A., Fawcett, K., Zelnik, N., Yuan, H., Thomposon, B., Shemer-Meiri, L., ... Pilz, D. T. (2018). De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain : A Journal of Neurology, 141(3), 698-712. https://doi.org/10.1093/brain/awx358

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. / Fry, Andrew; Fawcett, Katherine; Zelnik, Nathanel; Yuan, Hongjie; Thomposon, Belinda; Shemer-Meiri, Lilach; cushion, thomas; Mugalaasi, Hood; Sims, David; Stoodley, Neil; Chung, Seo-Kyung; Rees, Mark I.; Patel, Chirag V.; Brueton, Louise A.; Layet, Valerie; 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; Mullins, Jonathan G. L.; Lemke, Johannes R.; Bahi-Buisson, Nadia ; Traynelis, Stephen f.; Iago, Heledd F.; Pilz, Daniela T.

In: Brain : A Journal of Neurology, Vol. 141, No. 3, 31.03.2018, p. 698-712.

Research output: Contribution to journalArticle

Fry, A, Fawcett, K, Zelnik, N, Yuan, H, Thomposon, B, Shemer-Meiri, L, cushion, T, Mugalaasi, H, Sims, D, Stoodley, N, Chung, S-K, Rees, MI, Patel, CV, Brueton, LA, Layet, V, Giuliano, F, Kerr, MP, Banne, E, Meiner, V, Lerman-Sagie, T, Helbig, KL, Kofman, LH, Knight, KM, Chen, W, Kannan, V, Hu, C, Kusumoto, H, Zhang, J, Swanger, SA, Shaulsky, GH, Mirzaa, GM, Muir, AM, Mefford, HC, Dobyns, WB, Mackenzie, A, Mullins, JGL, Lemke, JR, Bahi-Buisson, N, Traynelis, SF, Iago, HF & Pilz, DT 2018, 'De novo mutations in GRIN1 cause extensive bilateral polymicrogyria', Brain : A Journal of Neurology, vol. 141, no. 3, pp. 698-712. https://doi.org/10.1093/brain/awx358
Fry A, Fawcett K, Zelnik N, Yuan H, Thomposon B, Shemer-Meiri L et al. De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain : A Journal of Neurology. 2018 Mar 31;141(3):698-712. https://doi.org/10.1093/brain/awx358
Fry, Andrew ; Fawcett, Katherine ; Zelnik, Nathanel ; Yuan, Hongjie ; Thomposon, Belinda ; Shemer-Meiri, Lilach ; cushion, thomas ; Mugalaasi, Hood ; Sims, David ; Stoodley, Neil ; Chung, Seo-Kyung ; Rees, Mark I. ; Patel, Chirag V. ; Brueton, Louise A. ; Layet, Valerie ; 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 ; 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. In: Brain : A Journal of Neurology. 2018 ; Vol. 141, No. 3. pp. 698-712.
@article{3f9d4b950f044820a7ab537d70c291fe,
title = "De novo mutations in GRIN1 cause extensive bilateral polymicrogyria",
abstract = "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.",
keywords = "GRIN1, GluN1, N -methyl- d -aspartate receptor, NR1, Polymicrogyria",
author = "Andrew Fry and Katherine Fawcett and Nathanel Zelnik and Hongjie Yuan and Belinda Thomposon and Lilach Shemer-Meiri and thomas cushion and Hood Mugalaasi and David Sims and Neil Stoodley and Seo-Kyung Chung and Rees, {Mark I.} and Patel, {Chirag V.} and Brueton, {Louise A.} and Valerie Layet and Fabienne Giuliano and Kerr, {Michael P.} and Ehud Banne and Vardiella Meiner and Tally Lerman-Sagie and Helbig, {Katherine L.} and Kofman, {Laura H.} and Knight, {Kristin M.} and Wenjuan Chen and Varun Kannan and Chun Hu and Hirofumi Kusumoto and Jin Zhang and Swanger, {Sharon A.} and Shaulsky, {Gil H.} and Mirzaa, {Ghayda M.} and Muir, {Alison M.} and Mefford, {Heather C.} and Dobyns, {William B.} and Amanda Mackenzie and Mullins, {Jonathan G. L.} and Lemke, {Johannes R.} and Nadia Bahi-Buisson and Traynelis, {Stephen f.} and Iago, {Heledd F.} and Pilz, {Daniela T.}",
note = "{\circledC} The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.",
year = "2018",
month = "3",
day = "31",
doi = "10.1093/brain/awx358",
language = "English",
volume = "141",
pages = "698--712",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - De novo mutations in GRIN1 cause extensive bilateral polymicrogyria

AU - Fry, Andrew

AU - Fawcett, Katherine

AU - Zelnik, Nathanel

AU - Yuan, Hongjie

AU - Thomposon, Belinda

AU - Shemer-Meiri, Lilach

AU - cushion, thomas

AU - Mugalaasi, Hood

AU - Sims, David

AU - Stoodley, Neil

AU - Chung, Seo-Kyung

AU - Rees, Mark I.

AU - Patel, Chirag V.

AU - Brueton, Louise A.

AU - Layet, Valerie

AU - Giuliano, Fabienne

AU - Kerr, Michael P.

AU - Banne, Ehud

AU - Meiner, Vardiella

AU - Lerman-Sagie, Tally

AU - Helbig, Katherine L.

AU - Kofman, Laura H.

AU - Knight, Kristin M.

AU - Chen, Wenjuan

AU - Kannan, Varun

AU - Hu, Chun

AU - Kusumoto, Hirofumi

AU - Zhang, Jin

AU - Swanger, Sharon A.

AU - Shaulsky, Gil H.

AU - Mirzaa, Ghayda M.

AU - Muir, Alison M.

AU - Mefford, Heather C.

AU - Dobyns, William B.

AU - Mackenzie, Amanda

AU - Mullins, Jonathan G. L.

AU - Lemke, Johannes R.

AU - Bahi-Buisson, Nadia

AU - Traynelis, Stephen f.

AU - Iago, Heledd F.

AU - Pilz, Daniela T.

N1 - © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2018/3/31

Y1 - 2018/3/31

N2 - 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.

AB - 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.

KW - GRIN1

KW - GluN1

KW - N -methyl- d -aspartate receptor

KW - NR1

KW - Polymicrogyria

UR - http://www.scopus.com/inward/record.url?scp=85042941228&partnerID=8YFLogxK

U2 - 10.1093/brain/awx358

DO - 10.1093/brain/awx358

M3 - Article

VL - 141

SP - 698

EP - 712

JO - Brain

JF - Brain

SN - 0006-8950

IS - 3

ER -