Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2016
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
_version_ 1782436331099521024
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
work_keys_str_mv AT lemkejohannesr delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT geiderkirsten delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT helbigkatherinel delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT heynehenrikeo delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT schutzhannah delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT hentscheljulia delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT couragecarolina delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT depiennechristel delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT navacaroline delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT herondelphine delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT møllerrikkes delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT hjalgrimhelle delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT laldennis delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT neubauerbernda delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT nurnbergpeter delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT thieleholger delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT kurlemanngerhard delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT arnoldgeorgiannel delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT bhambhanivikas delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT bartholdideborah delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT pedurupillaychristeenramanej delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT misceodoriana delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT frengeneirik delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT strømmepetter delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT dlugosdennisj delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT dohertyemilys delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT bijlsmaemiliak delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT ruivenkampclaudiaa delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT hoffermariettejv delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT goldsteinamy delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT rajandeepas delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT narayananvinodh delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT ramseykeri delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT belnapnewell delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT schrauwenisabelle delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT richholtryan delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT koelemanbobbypc delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT sajoaquim delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT mendoncacarla delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT dekovelcaroliengf delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT weckhuysensarah delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT hardieskatia delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT dejonghepeter delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT demeirleirlinda delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT milhmathieu delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT badenscatherine delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT lebrunmarine delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT busatiffany delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT francannetchristine delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT pitonamelie delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT riescherik delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT biskupsaskia delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT vogtheinrich delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT dornthomas delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT helbigingo delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT michaudjacquesl delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT laubebodo delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy
AT syrbesteffen delineatingthegrin1phenotypicspectrumadistinctgeneticnmdareceptorencephalopathy