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Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy

2016-06Journal article Open access
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dc.contributor.authorLemke, Johannes R.
dc.contributor.authorGeider, Kirsten
dc.contributor.authorHelbig, Katherine L.
dc.contributor.authorHeyne, Henrike O.
dc.contributor.authorSchutz, Hannah
dc.contributor.authorHentschel, Julia
dc.contributor.authorCourage, Carolina
dc.contributor.authorDepienne, Christel
dc.contributor.authorNava, Caroline
dc.contributor.authorHeron, Delphine
dc.contributor.authorMoller, Rikke S.
dc.contributor.authorHjalgrim, Helle
dc.contributor.authorLal, Dennis
dc.contributor.authorNeubauer, Bernd A.
dc.contributor.authorNurnberg, Peter
dc.contributor.authorThiele, Holger
dc.contributor.authorKurlemann, Gerhard
dc.contributor.authorArnold, Georgianne L.
dc.contributor.authorBhambhani, Vikas
dc.contributor.authorBartholdi, Deborah
dc.contributor.authorPedurupillay, Christeen Ramane J.
dc.contributor.authorMisceo, Doriana
dc.contributor.authorFrengen, Eirik
dc.contributor.authorStromme, Petter
dc.contributor.authorDlugos, Dennis J.
dc.contributor.authorDoherty, Emily S.
dc.contributor.authorBijlsma, Emilia K.
dc.contributor.authorRuivenkamp, Claudia A.
dc.contributor.authorHoffer, Mariette J. V.
dc.contributor.authorGoldstein, Amy
dc.contributor.authorRajan, Deepa S.
dc.contributor.authorNarayanan, Vinodh
dc.contributor.authorRamsey, Keri
dc.contributor.authorBelnap, Newell
dc.contributor.authorSchrauwen, Isabelle
dc.contributor.authorRichholt, Ryan
dc.contributor.authorKoeleman, Bobby P. C.
dc.contributor.authorSá, Joaquim
dc.contributor.authorMendonca, Carla
dc.contributor.authorde Kovel, Carolien G. F.
dc.contributor.authorWeckhuysen, Sarah
dc.contributor.authorHardies, Katia
dc.contributor.authorDe Jonghe, Peter
dc.contributor.authorDe Meirleir, Linda
dc.contributor.authorMilh, Mathieu
dc.contributor.authorBadens, Catherine
dc.contributor.authorLebrun, Marine
dc.contributor.authorBusa, Tiffany
dc.contributor.authorFrancannet, Christine
dc.contributor.authorPiton, Amelie
dc.contributor.authorRiesch, Erik
dc.contributor.authorBiskup, Saskia
dc.contributor.authorVogt, Heinrich
dc.contributor.authorDorn, Thomas
dc.contributor.authorHelbig, Ingo
dc.contributor.authorMichaud, Jacques L.
dc.contributor.authorLaube, Bodo
dc.contributor.authorSyrbe, Steffen
dc.date.accessioned2017-04-07T15:56:29Z
dc.date.available2017-04-07T15:56:29Z
dc.date.issued2016-06
dc.description.abstractObjective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.
dc.description.sponsorshipJohannes R. Lemke (32EP30_136042/1) and Peter De Jonghe (G.A.136.11.N and FWO/ESF-ECRP) received financial support within the EuroEPINOMICS-RES network (www.euroepinomics.org) within the Eurocores framework of the European Science Foundation (ESF). Saskia Biskup and Henrike Heyne received financial support from the German Federal Ministry for Education and Research (BMBF IonNeurONet: 01 GM1105A and FKZ: 01EO1501). Katia Hardies is a PhD fellow of the Institute for Science and Technology (IWT) Flanders. Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE). The project also received infrastructural support through the Institute of Clinical Molecular Biology in Kiel, supported in part by DFG Cluster of Excellence "Inflammation at Interfaces" and "Future Ocean." The project was also supported by the popgen 2.0 network (P2N) through a grant from the German Ministry for Education and Research (01EY1103) and by the International Coordination Action (ICA) grant G0E8614N. Christel Depienne, Caroline Nava, and Delphine Heron received financial support for exome analyses by the Centre National de Genotypage (CNG, Evry, France).
dc.identifier.doi10.1212/WNL.0000000000002740
dc.identifier.issn0028-3878
dc.identifier.urihttp://hdl.handle.net/10400.1/9427
dc.language.isoeng
dc.peerreviewedyes
dc.publisherLippincott, Williams & Wilkins
dc.relation.isbasedonWOS:000378417100015
dc.subjectDe-novo mutations
dc.subjectIntellectual disability
dc.subjectFocal epilepsy
dc.subjectDisorders
dc.subjectDiversity
dc.subjectSubunits
dc.subjectDiseases
dc.subjectAphasia
dc.subjectBinding
dc.titleDelineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage2178
oaire.citation.issue23
oaire.citation.startPage2171
oaire.citation.titleNeurology
oaire.citation.volume86
person.familyNameMendonca
person.givenNameCarla
person.identifier.ciencia-id2D17-DA8E-8484
person.identifier.orcid0000-0001-9926-0598
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublicationa8b3ae74-0a06-4585-a2ff-9b1097d65659
relation.isAuthorOfPublication.latestForDiscoverya8b3ae74-0a06-4585-a2ff-9b1097d65659

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