Lemke, Johannes R., Geider, Kirsten, Helbig, Katherine L., Heyne, Henrike O., Schutz, Hannah, Hentschel, Julia, Courage, Carolina, Depienne, Christel, Nava, Caroline ORCID: 0000-0003-1272-0518, Heron, Delphine, Moller, Rikke S., Hjalgrim, Helle, Lal, Dennis, Neubauer, Bernd A., Nurnberg, Peter, Thiele, Holger, Kurlemann, Gerhard, Arnold, Georgianne L., Bhambhani, Vikas, Bartholdi, Deborah, Pedurupillay, Christeen Ramane J., Misceo, Doriana, Frengen, Eirik ORCID: 0000-0002-8387-2247, Stromme, Petter, Dlugos, Dennis J., Doherty, Emily S., Bijlsma, Emilia K., Ruivenkamp, Claudia A., Hoffer, Mariette J. V., Goldstein, Amy, Rajan, Deepa S., Narayanan, Vinodh ORCID: 0000-0002-0658-3847, Ramsey, Keri, Belnap, Newell, Schrauwen, Isabelle ORCID: 0000-0001-7310-6082, Richholt, Ryan, Koeleman, Bobby P. C., Sa, Joaquim, Mendonca, Carla ORCID: 0000-0001-9926-0598, de Kovel, Carolien G. F., Weckhuysen, Sarah ORCID: 0000-0003-2878-1147, Hardies, Katia, De Jonghe, Peter, De Meirleir, Linda, Milh, Mathieu, Badens, Catherine ORCID: 0000-0001-9024-310X, Lebrun, Marine, Busa, Tiffany, Francannet, Christine, Piton, Amelie, Riesch, Erik, Biskup, Saskia, Vogt, Heinrich, Dorn, Thomas, Helbig, Ingo ORCID: 0000-0001-8486-0558, Michaud, Jacques L., Laube, Bodo and Syrbe, Steffen (2016). Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology, 86 (23). S. 2171 - 2179. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1526-632X

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Abstract

Objective: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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geider, KirstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, Katherine L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heyne, Henrike O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schutz, HannahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hentschel, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Courage, CarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Depienne, ChristelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nava, CarolineUNSPECIFIEDorcid.org/0000-0003-1272-0518UNSPECIFIED
Heron, DelphineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hjalgrim, HelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neubauer, Bernd A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nurnberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kurlemann, GerhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arnold, Georgianne L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bhambhani, VikasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartholdi, DeborahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedurupillay, Christeen Ramane J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Misceo, DorianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frengen, EirikUNSPECIFIEDorcid.org/0000-0002-8387-2247UNSPECIFIED
Stromme, PetterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dlugos, Dennis J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doherty, Emily S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bijlsma, Emilia K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruivenkamp, Claudia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffer, Mariette J. V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldstein, AmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rajan, Deepa S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Narayanan, VinodhUNSPECIFIEDorcid.org/0000-0002-0658-3847UNSPECIFIED
Ramsey, KeriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Belnap, NewellUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schrauwen, IsabelleUNSPECIFIEDorcid.org/0000-0001-7310-6082UNSPECIFIED
Richholt, RyanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeleman, Bobby P. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sa, JoaquimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mendonca, CarlaUNSPECIFIEDorcid.org/0000-0001-9926-0598UNSPECIFIED
de Kovel, Carolien G. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weckhuysen, SarahUNSPECIFIEDorcid.org/0000-0003-2878-1147UNSPECIFIED
Hardies, KatiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Meirleir, LindaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milh, MathieuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Badens, CatherineUNSPECIFIEDorcid.org/0000-0001-9024-310XUNSPECIFIED
Lebrun, MarineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Busa, TiffanyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Francannet, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piton, AmelieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riesch, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biskup, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogt, HeinrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorn, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDorcid.org/0000-0001-8486-0558UNSPECIFIED
Michaud, Jacques L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laube, BodoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Syrbe, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-272410
DOI: 10.1212/WNL.0000000000002740
Journal or Publication Title: Neurology
Volume: 86
Number: 23
Page Range: S. 2171 - 2179
Date: 2016
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1526-632X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DE-NOVO MUTATIONS; INTELLECTUAL DISABILITY; FOCAL EPILEPSY; DISORDERS; DIVERSITY; SUBUNITS; DISEASES; APHASIA; BINDINGMultiple languages
Clinical NeurologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27241

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