Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Neurology
2016 Jun 07;8623:2171-8. doi: 10.1212/WNL.0000000000002740.
Show Gene links
Show Anatomy links
Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.
Lemke JR
,
Geider K
,
Helbig KL
,
Heyne HO
,
Schütz H
,
Hentschel J
,
Courage C
,
Depienne C
,
Nava C
,
Heron D
,
Møller RS
,
Hjalgrim H
,
Lal D
,
Neubauer BA
,
Nürnberg P
,
Thiele H
,
Kurlemann G
,
Arnold GL
,
Bhambhani V
,
Bartholdi D
,
Pedurupillay CR
,
Misceo D
,
Frengen E
,
Strømme P
,
Dlugos DJ
,
Doherty ES
,
Bijlsma EK
,
Ruivenkamp CA
,
Hoffer MJ
,
Goldstein A
,
Rajan DS
,
Narayanan V
,
Ramsey K
,
Belnap N
,
Schrauwen I
,
Richholt R
,
Koeleman BP
,
Sá J
,
Mendonça C
,
de Kovel CG
,
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 JL
,
Laube B
,
Syrbe S
.
???displayArticle.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.
Figure 1. Domains of GRIN1 and distribution of variantsSignal peptide (SP), the extracellular N-terminal domain, and ligand binding sites (S1, S2), the transmembrane domains (M1-4), as well as the intracellular C-terminal domain (CTD) with the proximal Ca2+ calmodulin binding domain (CBD). De novo mutations (red) cluster within or in very close proximity to M1-4. In addition, this region is particularly spared from nonsynonymous genetic variation according to the ExAC browser (rare/single variants, gray; repeated/frequent variants, black). The 2 homozygous GRIN1 variants are marked in blue.
Allen,
De novo mutations in epileptic encephalopathies.
2013, Pubmed
Allen,
De novo mutations in epileptic encephalopathies.
2013,
Pubmed
Carvill,
GRIN2A mutations cause epilepsy-aphasia spectrum disorders.
2013,
Pubmed
Dalmau,
Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma.
2007,
Pubmed
Endele,
Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
2010,
Pubmed
Gleichman,
Anti-NMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain.
2012,
Pubmed
Hamdan,
Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.
2011,
Pubmed
Hardingham,
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders.
2010,
Pubmed
Laube,
Evidence for a tetrameric structure of recombinant NMDA receptors.
1998,
Pubmed
,
Xenbase
Laube,
Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit.
1997,
Pubmed
Laube,
Modulation by zinc ions of native rat and recombinant human inhibitory glycine receptors.
1995,
Pubmed
,
Xenbase
Lemke,
Targeted next generation sequencing as a diagnostic tool in epileptic disorders.
2012,
Pubmed
Lemke,
Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
2013,
Pubmed
,
Xenbase
Lemke,
GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.
2014,
Pubmed
,
Xenbase
Lesca,
GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.
2013,
Pubmed
O'Roak,
Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.
2011,
Pubmed
Ohba,
GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.
2015,
Pubmed
Paoletti,
Molecular basis of NMDA receptor functional diversity.
2011,
Pubmed
Paoletti,
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.
2013,
Pubmed
Redin,
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.
2014,
Pubmed
Tarabeux,
Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.
2011,
Pubmed
Yuan,
Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.
2015,
Pubmed
Zhu,
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.
2015,
Pubmed
de Ligt,
Diagnostic exome sequencing in persons with severe intellectual disability.
2012,
Pubmed
