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

Johannes R. Lemke , Kirsten Geider , Katherine L. Helbig (1) , Henrike O. Heyne , Hannah Schutz , Julia Hentschel , Carolina Courage , Christel Depienne (2, 3) , Caroline Nava (2, 4) , Delphine Héron (2, 5) , Rikke S. Moller , Helle Hjalgrim (6) , Dennis Lal (7, 8) , Bernd A. Neubauer , Peter Nürnberg (9, 10, 11) , Holger Thiele (12) , Gerhard Kurlemann , Georgianne L. Arnold , Vikas Bhambhani , Deborah Bartholdi (13) , Christeen Ramane J. Pedurupillay , Doriana Misceo , Eirik Frengen , Petter Stromme , Dennis J. Dlugos , Emily S. Doherty , Emilia K. Bijlsma , Claudia A. Ruivenkamp , Mariette J. V. Hoffer , Amy Goldstein (14) , Deepa S. Rajan , Vinodh Narayanan , Keri Ramsey , Newell Belnap , Isabelle Schrauwen , Ryan Richholt , Bobby P. C. Koeleman , Joaquim Sa , Carla Mendonca , Carolien G. F. De Kovel , Sarah Weckhuysen (3, 2) , Katia Hardies (15, 16) , Peter de Jonghe (17, 18) , Linda de Meirleir (19) , Mathieu Milh (20, 21) , Catherine Badens (21, 22, 23) , Marine Lebrun (24) , Tiffany Busa (21) , Christine Francannet (25) , Amélie Piton (26) , Erik Riesch , Saskia Biskup (27, 28) , Heinrich Vogt , Thomas Dorn , Ingo Helbig (29, 30) , Jacques L. Michaud , Bodo Laube , Steffen Syrbe

1 University of Calgary
2 CHU Pitié-Salpêtrière [AP-HP]
3 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
4 UPMC - Université Pierre et Marie Curie - Paris 6
5 GRC 9 - Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)
6 Medical Genetics Laboratory
7 Cologne Center for Genomics
8 Department of Neuropediatrics
9 Cologne Center for Genomics
10 Center for Molecular Medicine Cologne
11 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases
12 University of Cologne
13 Institute of Medical Genetics
14 Children's Hospital of Pittsburgh
15 VIB11 - Department of Molecular and Developmental Genetics
16 Institute Born-Bunge
17 UZA - Antwerp University Hospital [Edegem]
18 Neurogenetics Group
19 Pediatric neurology- metabolic diseases
20 Service de pédiatrie et neurologie pédiatrique
21 GMGF - Génétique Médicale et Génomique Fonctionnelle
22 Département de génétique médicale [Hôpital de la Timone - APHM]
23 Centre de référence maladie rare Thalassémie
24 Service de Génétique Clinique Chromosomique et Moléculaire
25 Génétique Médicale
26 Laboratoire de Génétique Moléculaire [CHRU Strasbourg]
27 Institute of Medical Genetics
28 Department of Neurodegenerative Diseases
29 CHOP - Children’s Hospital of Philadelphia
30 Department of Neuropediatrics

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.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]

Johannes R. Lemke, Kirsten Geider, Katherine L. Helbig, Henrike O. Heyne, Hannah Schutz, et al.. Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology, 2016, 86 (23), pp.2171-2178. ⟨10.1212/WNL.0000000000002740⟩. ⟨hal-01469047⟩