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Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.

Lemke, Johannes R. and Geider, Kirsten and Helbig, Katherine L. and Heyne, Henrike O. and Schütz, Hannah and Hentschel, Julia and Courage, Carolina and Depienne, Christel and Nava, Caroline and Heron, Delphine and Møller, Rikke S. and Hjalgrim, Helle and Lal, Dennis and Neubauer, Bernd A. and Nürnberg, Peter and Thiele, Holger and Kurlemann, Gerhard and Arnold, Georgianne L. and Bhambhani, Vikas and Bartholdi, Deborah and Pedurupillay, Christeen Ramane J. and Misceo, Doriana and Frengen, Eirik and Strømme, Petter and Dlugos, Dennis J. and Doherty, Emily S. and Bijlsma, Emilia K. and Ruivenkamp, Claudia A. and Hoffer, Mariette J. V. and Goldstein, Amy and Rajan, Deepa S. and Narayanan, Vinodh and Ramsey, Keri and Belnap, Newell and Schrauwen, Isabelle and Richholt, Ryan and Koeleman, Bobby P. C. and Sá, Joaquim and Mendonça, Carla and de Kovel, Carolien G. F. and Weckhuysen, Sarah and Hardies, Katia and De Jonghe, Peter and De Meirleir, Linda and Milh, Mathieu and Badens, Catherine and Lebrun, Marine and Busa, Tiffany and Francannet, Christine and Piton, Amélie and Riesch, Erik and Biskup, Saskia and Vogt, Heinrich and Dorn, Thomas and Helbig, Ingo and Michaud, Jacques L. and Laube, Bodo and Syrbe, Steffen (2016):
Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.
In: Neurology, pp. 2171-8, 86, (23), ISSN 1526-632X,
[Article]

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: Article
Erschienen: 2016
Creators: Lemke, Johannes R. and Geider, Kirsten and Helbig, Katherine L. and Heyne, Henrike O. and Schütz, Hannah and Hentschel, Julia and Courage, Carolina and Depienne, Christel and Nava, Caroline and Heron, Delphine and Møller, Rikke S. and Hjalgrim, Helle and Lal, Dennis and Neubauer, Bernd A. and Nürnberg, Peter and Thiele, Holger and Kurlemann, Gerhard and Arnold, Georgianne L. and Bhambhani, Vikas and Bartholdi, Deborah and Pedurupillay, Christeen Ramane J. and Misceo, Doriana and Frengen, Eirik and Strømme, Petter and Dlugos, Dennis J. and Doherty, Emily S. and Bijlsma, Emilia K. and Ruivenkamp, Claudia A. and Hoffer, Mariette J. V. and Goldstein, Amy and Rajan, Deepa S. and Narayanan, Vinodh and Ramsey, Keri and Belnap, Newell and Schrauwen, Isabelle and Richholt, Ryan and Koeleman, Bobby P. C. and Sá, Joaquim and Mendonça, Carla and de Kovel, Carolien G. F. and Weckhuysen, Sarah and Hardies, Katia and De Jonghe, Peter and De Meirleir, Linda and Milh, Mathieu and Badens, Catherine and Lebrun, Marine and Busa, Tiffany and Francannet, Christine and Piton, Amélie and Riesch, Erik and Biskup, Saskia and Vogt, Heinrich and Dorn, Thomas and Helbig, Ingo and Michaud, Jacques L. and Laube, Bodo and Syrbe, Steffen
Title: Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.
Language: English
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.

Journal or Publication Title: Neurology
Volume: 86
Number: 23
Divisions: 10 Department of Biology
10 Department of Biology > Neurophysiology and Neurosensory Systems
Date Deposited: 26 Jul 2016 07:47
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