Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes

Endele, Sabine; Rosenberger, Georg; Geider, Kirsten; Popp, Bernt; Tamer, Ceyhun; Stefanova, Irina; Milh, Mathieu; Kortüm, Fanny; Fritsch, Angela; Pientka, Friederike Katharina; Hellenbroich, Yorck; Kalscheuer, Vera M.; Kohlhase, Jürgen; Moog, Ute; Rappold, Gudrun; Rauch, Anita; Ropers, Hans Hilger; Spiczak, Sarah von; Tönnies, Holger; Villeneuve, Nathalie; Villard, Laurent; Zabel, Bernhard; Zenker, Martin; Laube, Bodo; Reis, André; Wieczorek, Dagmar; Maldergem, Lionel Van; Kutsche, Kerstin

doi:10.1038/ng.677

Cited by 448 publications

(473 citation statements)

References 35 publications

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“…Variants in GRIN2B have previously been found in individuals with ID. 46 GRIN2B encodes the subunit NR2B of the NMDA receptor, which is present during development. In the first decade, during the critical period of developing cerebral visual cortex, NR2B is replaced by NR2A, encoded by GRIN2A.…”

Section: Resultsmentioning

confidence: 99%

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Novel genetic causes for cerebral visual impairment

et al. 2015

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Section: Resultsmentioning

confidence: 99%

“…So far, 18 patients with GRIN2B variants have been reported. 17,18,46,[49][50][51][52] In two patients with West syndrome, poor eye contact was reported, 50 whereas in the other patients no assessment for CVI or visual acuity measurement was mentioned.…”

Section: Resultsmentioning

confidence: 99%

Novel genetic causes for cerebral visual impairment

et al. 2015

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“…The heterozygous missense variant p.(Ala243Val) in GRIN2A has been shown to significantly reduce high-affinity Zn 2+ inhibition, mediating a gain-of-function. 6 For the c.679G4C variant, which is located in GRIN1 in a position similar to p.(Ala243Val) in GRIN2A, we could rather expect a loss-of-function mechanism. Functional studies, however, would be useful to answer this question.…”

Section: Discussionmentioning

confidence: 99%

Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy

et al. 2017

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We report on two consanguineous sibs affected with severe intellectual disability and autistic features due to a homozygous missense variant of GRIN1. Massive parallel sequencing was performed using a gene panel including 450 genes related to intellectual disability and autism spectrum disorders. We found a homozygous missense variation of GRIN1 (c.679G4C; p.(Asp227His)) in the two affected sibs, which was inherited from both unaffected heterozygous parents. Heterozygous variants of GRIN1, encoding the GluN1 subunit of the NMDA receptor, have been reported in patients with neurodevelopmental disorders including epileptic encephalopathy, severe intellectual disability, and movement disorders. The p.(Asp227His) variant is located in the same aminoterminal protein domain as the recently published p.(Arg217Trp), which was found at the homozygous state in two patients with a similar phenotype of severe intellectual disability and autistic features but without epilepsy. In silico predictions were consistent with a deleterious effect. The present findings further expand the clinical spectrum of GRIN1 variants and support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance. European Journal of Human Genetics (2017) 25, 376-380; doi:10.1038/ejhg.2016.163; published online 4 January 2017 INTRODUCTION GRIN1 (MIM *138249) encodes the GluN1 subunit of N-methyl-Daspartate receptors, members of the glutamate receptor channel superfamily, which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits have a key role in the plasticity of synapses, which underlies memory and learning. 1 De novo heterozygous variants of GRIN1 were first identified by targeted Sanger sequencing in two patients with intellectual disability (ID) with or without epilepsy (MIM #614254). 2 Recent advances in nextgeneration sequencing have shown that GRIN1 de novo heterozygous variants represent a recurrent cause of epileptic encephalopathy with early onset. 3,4 A recent paper provided a better delineation of the GRIN1 phenotypic spectrum that includes severe ID with absent speech, muscular hypotonia, hyperkinetic movements, oculogyric crises, hand stereotypies, cortical blindness, and epilepsy. 5 This article also reported for the first time two homozygous GRIN1 variants in families with severe neurodevelopmental phenotypes.In the present paper we report a second family including two affected sibs with a homozygous missense variant, thus expanding the phenotype-genotype correlations related to GRIN1 variants.

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“…For these eight genes, it is either gain-of-function or dominant negative, thereby showing statistical enrichment for NHI mechanisms (p ¼ 2.66E-03, Fisher's exact test; Table S14 and S15). For two of the three remaining genes (GRIN2B [MIM 138252] and SMAD4 [MIM 600993]) both HI and NHI consequences have been reported, [36][37][38][39] suggesting that for mutations in these genes more complex genotype-phenotype relations might exist, where HI and NHI mechanisms cause clinically distinct ID/DD-related disorders. For KCNQ2 (MIM 602235), the reported mutational mechanism is HI although a literature search also revealed cases with dominant-negative effects.…”

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Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

Lelieveld

Wiel

Venselaar

et al. 2017

The American Journal of Human Genetics

101

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SummaryHaploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. Here we exploit this property and develop a method to specifically identify genes with significant spatial clustering patterns of de novo mutations in large cohorts. We apply our method to a dataset of 4,061 de novo missense mutations from published exome studies of trios with intellectual disability and developmental disorders (ID/DD) and successfully identify 15 genes with clustering mutations, including 12 genes for which mutations are known to cause neurodevelopmental disorders. For 11 out of these 12, NHI mutation mechanisms have been reported. Additionally, we identify three candidate ID/DD-associated genes of which two have an established role in neuronal processes. We further observe a higher intolerance to normal genetic variation of the identified genes compared to known genes for which mutations lead to HI. Finally, 3D modeling of these mutations on their protein structures shows that 81% of the observed mutations are unlikely to affect the overall structural integrity and that they therefore most likely act through a mechanism other than HI.De novo mutations affecting protein-coding genes are a major cause of intellectual disability (ID) and other developmental disorders (DDs). We downloaded all DNMs occurring in individuals with ID/DD from de novo-db version 1.3 14 identified through WES and whole genome sequencing which were then reannotated with our in-house variant annotation pipeline. The de novo mutations included in the analysis were previously validated by a second independent method or showed a high validation rate for a subset of de novo mutations. In addition, we added 1,183 de novo variants identified in the exomes of an in-house ID cohort that was previously published. 8 To further reduce the risk of including sequencing artifacts and/or genotyping errors, we excluded all de novo variants that were present more than once in the ExAC dataset (Table S1). 15 These efforts resulted in 6,495 protein coding DNMs, including 4,061 missense mutations, in 5,302 individuals with ID/DD (Table S2). We set out to determine for any gene whether the observed de novo missense mutations cluster more than expected compared to random permutations. Hereto, we selected for each the longest representative transcript (i.e., part of the GENCODE basic set) 16 and calculated the geometric mean distance d g over all missense DNMs on

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Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes

Cited by 448 publications

References 35 publications

Novel genetic causes for cerebral visual impairment

Novel genetic causes for cerebral visual impairment

Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

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