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

Autor: Keri Ramsey, Dennis J. Dlugos, Bodo Laube, Carolien G.F. de Kovel, Deborah Bartholdi, Carla Mendonça, Marine Lebrun, Doriana Misceo, Johannes R. Lemke, Christeen Ramane J. Pedurupillay, Vinodh Narayanan, Petter Strømme, Thomas Dorn, Carolina Courage, Ingo Helbig, Peter De Jonghe, Joaquim Sa, Jacques L. Michaud, Heinrich Vogt, Deepa S. Rajan, Peter Nürnberg, Emilia K. Bijlsma, Vikas Bhambhani, Claudia A. L. Ruivenkamp, Sarah Weckhuysen, Steffen Syrbe, Newell Belnap, Bobby P. C. Koeleman, Isabelle Schrauwen, Catherine Badens, Amélie Piton, Delphine Héron, Amy Goldstein, Gerhard Kurlemann, Dennis Lal, Bernd A. Neubauer, Holger Thiele, Tiffany Busa, Georgianne L. Arnold, Emily S. Doherty, Julia Hentschel, Saskia Biskup, Mariëtte J.V. Hoffer, Helle Hjalgrim, Henrike O. Heyne, Christel Depienne, Ryan Richholt, Christine Francannet, Caroline Nava, Rikke S. Møller, Erik Riesch, Eirik Frengen, Kirsten Geider, Katherine L. Helbig, Mathieu Milh, Hannah Schütz, Katia Hardies, Linda De Meirleir
Přispěvatelé: University of Calgary, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Medical Genetics Laboratory, Cologne Center for Genomics, University of Cologne, Department of Neuropediatrics, Center for Molecular Medicine Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Children's Hospital of Pittsburgh, Department of Molecular and Developmental Genetics (VIB11), Flanders institute of biotechnology, Institute Born-Bunge, University of Antwerp (UA), Antwerp University Hospital [Edegem] (UZA), Neurogenetics Group, Pediatric neurology- metabolic diseases, UZ Brussel, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence maladie rare Thalassémie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Génétique Médicale, CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Department of Neurodegenerative Diseases, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Children’s Hospital of Philadelphia (CHOP ), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cologne Center for Genomics (CCG), University of Cologne, Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], CHU Saint-Etienne, Reproduction and Genetics, Neurogenetics, Clinical sciences, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière]
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Neurology
Neurology, 2016, 86 (23), pp.2171-2178. ⟨10.1212/WNL.0000000000002740⟩
Neurology, American Academy of Neurology, 2016, 86 (23), pp.2171-2178. ⟨10.1212/WNL.0000000000002740⟩
Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
Neurology, 86(23), 2171. Lippincott Williams and Wilkins
Lemke, J R, Geider, K, Helbig, K L, Heyne, H O, Schütz, H, Hentschel, J, Courage, C, Depienne, C, Nava, C, Heron, D, Møller, R S, Hjalgrim, H, Lal, D, Neubauer, B A, Nürnberg, P, Thiele, H, Kurlemann, G, Arnold, G L, Bhambhani, V, Bartholdi, D, Pedurupillay, C R J, Misceo, D, Frengen, E, Strømme, P, Dlugos, D J, Doherty, E S, Bijlsma, E K, Ruivenkamp, C A, Hoffer, M J V, Goldstein, A, Rajan, D S, Narayanan, V, Ramsey, K, Belnap, N, Schrauwen, I, Richholt, R, Koeleman, B P C, Sá, J, Mendonça, C, de Kovel, C G F, Weckhuysen, S, Hardies, K, De Jonghe, P, De Meirleir, L, Milh, M, Badens, C, Lebrun, M, Busa, T, Francannet, C, Piton, A, Riesch, E, Biskup, S, Vogt, H, Dorn, T, Helbig, I, Michaud, J L, Laube, B & Syrbe, S 2016, ' Delineating the GRIN1 phenotypic spectrum : A distinct genetic NMDA receptor encephalopathy ', Neurology, vol. 86, no. 23, pp. 2171-2178 . https://doi.org/10.1212/WNL.0000000000002740
Neurology, 86(23), 2171-2178
ISSN: 0028-3878
1526-632X
DOI: 10.1212/WNL.0000000000002740⟩
Popis: 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. Johannes 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).
Databáze: OpenAIRE
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