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Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy
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 consequence...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898312/ https://www.ncbi.nlm.nih.gov/pubmed/27164704 http://dx.doi.org/10.1212/WNL.0000000000002740 |
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author | Lemke, Johannes R. Geider, Kirsten Helbig, Katherine L. Heyne, Henrike O. Schütz, Hannah Hentschel, Julia Courage, Carolina Depienne, Christel Nava, Caroline Heron, Delphine Møller, Rikke S. Hjalgrim, Helle Lal, Dennis Neubauer, Bernd A. Nürnberg, Peter Thiele, Holger Kurlemann, Gerhard Arnold, Georgianne L. Bhambhani, Vikas Bartholdi, Deborah Pedurupillay, Christeen Ramane J. Misceo, Doriana Frengen, Eirik Strømme, Petter Dlugos, Dennis J. Doherty, Emily S. Bijlsma, Emilia K. Ruivenkamp, Claudia A. Hoffer, Mariette J.V. Goldstein, Amy Rajan, Deepa S. Narayanan, Vinodh Ramsey, Keri Belnap, Newell Schrauwen, Isabelle Richholt, Ryan Koeleman, Bobby P.C. Sá, Joaquim Mendonça, Carla de Kovel, Carolien G.F. Weckhuysen, Sarah Hardies, Katia De Jonghe, Peter De Meirleir, Linda Milh, Mathieu Badens, Catherine Lebrun, Marine Busa, Tiffany Francannet, Christine Piton, Amélie Riesch, Erik Biskup, Saskia Vogt, Heinrich Dorn, Thomas Helbig, Ingo Michaud, Jacques L. Laube, Bodo Syrbe, Steffen |
author_facet | Lemke, Johannes R. Geider, Kirsten Helbig, Katherine L. Heyne, Henrike O. Schütz, Hannah Hentschel, Julia Courage, Carolina Depienne, Christel Nava, Caroline Heron, Delphine Møller, Rikke S. Hjalgrim, Helle Lal, Dennis Neubauer, Bernd A. Nürnberg, Peter Thiele, Holger Kurlemann, Gerhard Arnold, Georgianne L. Bhambhani, Vikas Bartholdi, Deborah Pedurupillay, Christeen Ramane J. Misceo, Doriana Frengen, Eirik Strømme, Petter Dlugos, Dennis J. Doherty, Emily S. Bijlsma, Emilia K. Ruivenkamp, Claudia A. Hoffer, Mariette J.V. Goldstein, Amy Rajan, Deepa S. Narayanan, Vinodh Ramsey, Keri Belnap, Newell Schrauwen, Isabelle Richholt, Ryan Koeleman, Bobby P.C. Sá, Joaquim Mendonça, Carla de Kovel, Carolien G.F. Weckhuysen, Sarah Hardies, Katia De Jonghe, Peter De Meirleir, Linda Milh, Mathieu Badens, Catherine Lebrun, Marine Busa, Tiffany Francannet, Christine Piton, Amélie Riesch, Erik Biskup, Saskia Vogt, Heinrich Dorn, Thomas Helbig, Ingo Michaud, Jacques L. Laube, Bodo Syrbe, Steffen |
author_sort | Lemke, Johannes R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4898312 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-48983122016-06-15 Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy Lemke, Johannes R. Geider, Kirsten Helbig, Katherine L. Heyne, Henrike O. Schütz, Hannah Hentschel, Julia Courage, Carolina Depienne, Christel Nava, Caroline Heron, Delphine Møller, Rikke S. Hjalgrim, Helle Lal, Dennis Neubauer, Bernd A. Nürnberg, Peter Thiele, Holger Kurlemann, Gerhard Arnold, Georgianne L. Bhambhani, Vikas Bartholdi, Deborah Pedurupillay, Christeen Ramane J. Misceo, Doriana Frengen, Eirik Strømme, Petter Dlugos, Dennis J. Doherty, Emily S. Bijlsma, Emilia K. Ruivenkamp, Claudia A. Hoffer, Mariette J.V. Goldstein, Amy Rajan, Deepa S. Narayanan, Vinodh Ramsey, Keri Belnap, Newell Schrauwen, Isabelle Richholt, Ryan Koeleman, Bobby P.C. Sá, Joaquim Mendonça, Carla de Kovel, Carolien G.F. Weckhuysen, Sarah Hardies, Katia De Jonghe, Peter De Meirleir, Linda Milh, Mathieu Badens, Catherine Lebrun, Marine Busa, Tiffany Francannet, Christine Piton, Amélie Riesch, Erik Biskup, Saskia Vogt, Heinrich Dorn, Thomas Helbig, Ingo Michaud, Jacques L. Laube, Bodo Syrbe, Steffen Neurology Article 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. Lippincott Williams & Wilkins 2016-06-07 /pmc/articles/PMC4898312/ /pubmed/27164704 http://dx.doi.org/10.1212/WNL.0000000000002740 Text en © 2016 American Academy of Neurology This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially. |
spellingShingle | Article Lemke, Johannes R. Geider, Kirsten Helbig, Katherine L. Heyne, Henrike O. Schütz, Hannah Hentschel, Julia Courage, Carolina Depienne, Christel Nava, Caroline Heron, Delphine Møller, Rikke S. Hjalgrim, Helle Lal, Dennis Neubauer, Bernd A. Nürnberg, Peter Thiele, Holger Kurlemann, Gerhard Arnold, Georgianne L. Bhambhani, Vikas Bartholdi, Deborah Pedurupillay, Christeen Ramane J. Misceo, Doriana Frengen, Eirik Strømme, Petter Dlugos, Dennis J. Doherty, Emily S. Bijlsma, Emilia K. Ruivenkamp, Claudia A. Hoffer, Mariette J.V. Goldstein, Amy Rajan, Deepa S. Narayanan, Vinodh Ramsey, Keri Belnap, Newell Schrauwen, Isabelle Richholt, Ryan Koeleman, Bobby P.C. Sá, Joaquim Mendonça, Carla de Kovel, Carolien G.F. Weckhuysen, Sarah Hardies, Katia De Jonghe, Peter De Meirleir, Linda Milh, Mathieu Badens, Catherine Lebrun, Marine Busa, Tiffany Francannet, Christine Piton, Amélie Riesch, Erik Biskup, Saskia Vogt, Heinrich Dorn, Thomas Helbig, Ingo Michaud, Jacques L. Laube, Bodo Syrbe, Steffen Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy |
title | Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy |
title_full | Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy |
title_fullStr | Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy |
title_full_unstemmed | Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy |
title_short | Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy |
title_sort | delineating the grin1 phenotypic spectrum: a distinct genetic nmda receptor encephalopathy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898312/ https://www.ncbi.nlm.nih.gov/pubmed/27164704 http://dx.doi.org/10.1212/WNL.0000000000002740 |
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