De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy

Zehavi, Yoav; Mandel, Hanna; Zehavi, A.; Rashid, Muhammad Abu; Straussberg, Rachel; Jabur, Banan; Shaag, Avraham; Elpeleg, Orly; Spiegel, Ronen

doi:10.1016/j.ejmg.2017.04.001

Cited by 36 publications

(46 citation statements)

References 14 publications

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“…We also identified 4/16 patients in the Dravet cohort with pathogenic variants in HCN1, PCDH19, GRIN1, and CHD2. The GRIN1 gene, which maps to 9q34.3 and encodes the glutamate ionotropic receptor NMDA type subunit 1, was recently associated with intellectual disability and epileptic encephalopathy [11][12][13][14]. Patients with GRIN1 pathogenic variants are documented with various epileptic phenotypes, including infantile spasms, tonic and atonic seizures, generalized seizures, status epilepticus, and febrile seizures [11].…”

Section: Discussionmentioning

confidence: 99%

Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: Identification of a new KCND3 phenotype and novel genes causing Dravet syndrome

Wang

Wen

Zhang

et al. 2019

Seizure

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A B S T R A C TPurpose: This study aimed to investigate the genetic etiology of epilepsy in a cohort of Chinese children. Methods: Targeted next-generation sequencing (NGS) was performed for 120 patients with unexplained epilepsy, including 71 patients with early-onset epileptic encephalopathies, and 16 patients with Dravet syndrome (including three patients with a Dravet-like phenotype) but without SCN1A pathogenic variants. Results: Pathogenic variants of 14 genes were discovered in 22 patients (18%). A de novo KCND3 pathogenic variant (c.1174G > A, p.Val392Ile) was identified in a boy with refractory epilepsy, psychomotor regression, attention deficit, and visual decline. Pathogenic variants in other coding genes were excluded via whole exome sequencing. This KCND3 variant was previously confirmed to be pathogenic by Giudicessi, et al. However, the clinical profile was different: sudden death at 20 years old without any medical history of neurological disorders, nor with any diseases typically caused by KCND3 pathogenic variants such as Brugada syndrome, spinocerebellar ataxia type 19/22 or ataxia accompanied by epilepsy. This indicates that we have identified a new KCND3 phenotype. In addition, we also uncovered a GRIN1 pathogenic variant and a novel HCN1 pathogenic variant in the Dravet cohort. Conclusion: Our study highlights the significant utility of NGS panels in the genetic diagnosis of pediatric epilepsy. Our findings indicate that KCND3 pathogenic variants may be responsible for a wider phenotypic spectrum than previously thought, by including childhood epileptic encephalopathy. Furthermore, this study provides evidence that GRIN1 and HCN1 are candidate genes for Dravet and Dravet-like phenotypes.

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Section: Discussionmentioning

confidence: 99%

Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: Identification of a new KCND3 phenotype and novel genes causing Dravet syndrome

Wang

Wen

Zhang

et al. 2019

Seizure

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“…Our results suggest a role of Grin1 Nterminal splicing in brain disease. Several mutations of GRIN1 have been associated with neurodevelopmental disorders (53)(54)(55). However, none of these mutations are in exon 5 or affect exon 5 splicing.…”

Section: Discussionmentioning

confidence: 99%

N-terminal alternative splicing of GluN1 regulates the maturation of excitatory synapses and seizure susceptibility

Liu

Wang

Peterson

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The majority of NMDA receptors (NMDARs) in the brain are composed of 2 GluN1 and 2 GluN2 subunits. The inclusion or exclusion of 1 N-terminal and 2 C-terminal domains of GluN1 results in 8 splicing variants that exhibit distinct temporal and spatial patterns of expression and functional properties. However, previous functional analyses of Grin1 variants have been done using heterologous expression and the in vivo function of Grin1 splicing is unknown. Here we show that N-terminal splicing of GluN1 has important functions in the maturation of excitatory synapses. The inclusion of exon 5 of Grin1 is up-regulated in several brain regions such as the thalamus and neocortex. We find that deletion of Grin1 exon 5 disrupts the developmental remodeling of NMDARs in thalamic neurons and the effect is distinct from that of Grin2a (GluN2A) deletion. Deletion of Grin2a or exon 5 of Grin1 alone partially attenuates the shortening of NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) during early life, whereas deletion of both Grin2a and exon 5 of Grin1 completely abolishes the developmental change in NMDAR-EPSC decay time. Deletion of exon 5 of Grin1 leads to an overproduction of excitatory synapses in layer 5 pyramidal neurons in the cortex and increases seizure susceptibility in adult mice. Our findings demonstrate that N-terminal splicing of GluN1 has important functions in synaptic maturation and neuronal network excitability.

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“…54,55 Here, patients also present with extrapyramidal features including choreoathetosis, ataxia, hand stereotypies, and atypical eye movements. [63][64][65] Genes involved in synaptic vesicle dynamics Genotype-phenotype correlation suggests that mutations with greater impact on GABRB2 activity appear to cause the more severe DEE phenotype.…”

Section: Sodium Channel Genesmentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

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De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy

Cited by 36 publications

References 14 publications

Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: Identification of a new KCND3 phenotype and novel genes causing Dravet syndrome

Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: Identification of a new KCND3 phenotype and novel genes causing Dravet syndrome

N-terminal alternative splicing of GluN1 regulates the maturation of excitatory synapses and seizure susceptibility

The expanding spectrum of movement disorders in genetic epilepsies

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