AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Salpietro, Vincenzo; Dixon, Curt B.; Guo, Hui; Bello, Oscar; Vandrovcová, Jana; Efthymiou, Stéphanie; Maroofian, Reza; Heimer, Gali; Bürglen, Lydie; Valence, Stéphanie; Torti, Erin; Hacke, Moritz; Rankin, Julia; Tariq, Huma; Colin, Estelle; Procaccio, Vincent; Striano, Pasquale; Mankad, Kshitij; Lieb, Andreas; Chen, Sharon; Pisani, Laura Rosa; Bettencourt, Conceição; Männikkö, Roope; Manole, Andreea; Brusco, Alfredo; Grosso, Enrico; Ferrero, Giovanni Battista; Armstrong-Morón, Judith; Guéden, Sophie; Bar‐Yosef, Omer; Tzadok, Michal; Monaghan, Kristin G.; Santiago‐Sim, Teresa; Person, Richard; Cho, Megan T.; Willaert, Rebecca; Yoo, Yongjin; Chae, Jong‐Hee; Quan, Yingting; Wu, Huidan; Wang, Tianyun; Bernier, Raphael; Xia, Kun; Blesson, Alyssa; Jain, Mahim; Motazacker, Mohammad Mahdi; Jaeger, Bregje; Schneider, Amy; Boysen, Katja; Muir, Alison M.; Myers, Candace T.; Gavrilova, Ralitza H.; Gunderson, Lauren; Schultz‐Rogers, Laura; Klee, Eric W.; Dyment, David A.; Osmond, Matthew; Parellada, Mara; Llorente, Cloe; González-Peñas, Javier; Carracedo, Ángel; Haeringen, Arie van; Ruivenkamp, Claudia; Nava, Caroline; Héron, Delphine; Nardello, Rosaria; Iacomino, Michele; Minetti, Carlo; Skabar, Aldo; Fabretto, Antonella; Raspall-Chaure, Miquel; Chez, Michael G.; Tsai, Anne Chun-Hui; Fassi, Emily; Shinawi, Marwan; Constantino, John N.; Zorzi, Rita De; Fortuna, Sara; Kok, Fernando; Keren, Boris; Bonneau, Dominique; Choi, Murim; Ben‐Zeev, Bruria; Zara, Federico; Mefford, Heather C; Scheffer, Ingrid E.; Clayton‐Smith, Jill; Macaya, Alfons; Rothman, James E.; Eichler, Evan E.; Kullmann, Dimitri M.; Houlden, Henry

doi:10.1038/s41467-019-10910-w

Cited by 156 publications

(118 citation statements)

References 65 publications

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“…We comprehensively characterized the clinical features and variants in six families with biallelic variants in GRM7 and showed that rare GRM7 biallelic variants can cause a severe neurological phenotype characterized by microcephaly, DEE, hypomyelination, and cerebral atrophy. Overall, the findings of both congenital neuroimaging features such as under‐opercularization and thin corpus callosum and progressive features such as cerebral atrophy suggest that GRM7 ‐related disorders are both congenital and progressive in nature similar to that seen in GRIA2‐ related NDDs 7 . Additionally, other disorders such as CDKL5 ‐related and FOXG1 ‐related disorders cause a wide and heterogeneous range of NDDs 29,30 .…”

Section: Discussionmentioning

confidence: 86%

“…Excessive glutamate is also neurotoxic, potentially explaining the marked and early progressive cerebral atrophy and axonal loss observed in our subjects, particularly the affected siblings in Family 2 with the observations of longitudinal MRI data and the acquired microcephaly pattern in one of them. Interestingly, postnatal deceleration of head growth has been observed in 5/28 subjects with deleterious monoallelic variants in GRIA2 , a gene encoding a subunit of another glutamate receptor, AMPAR 7 . However, our ability to further assess or quantify this finding is limited due to the lack of longitudinal data in other subjects.…”

Section: Discussionmentioning

confidence: 99%

“…KAR is thought to play a role in presynaptic and postsynaptic modulation of neurotransmission 36 . De novo and inherited pathogenic variations in genes encoding postsynaptic iGluRs subunits cause a wide range of NDDs and DEEs 4–10 . Interestingly, biochemical and in vitro functional assays show that variants in the same gene encoding some NMDAR and AMPAR subunits (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…The iGluRs include N‐methyl‐D‐aspartate receptor (NMDAR), alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR), and kainate receptor (KAR). Rare monoallelic and biallelic single nucleotide variants (SNVs) and copy number variants (CNVs) in genes encoding postsynaptic iGluRs subunits such as GRIN1, GRIN2A , GRIN2B , and GRIN2D encoding the NR1, NR2A, NR2B, and NR2D subunits of NMDAR, respectively, GRIA2‐4 encoding the GluR2‐4 subunits of AMPAR, and GRIK2 encoding the GluR6 subunit of KAR have been shown to cause a wide range of neurodevelopmental disorders (NDDs) and DEEs 4–11 …”

Section: Introductionmentioning

confidence: 99%

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Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Marafi

Mitani

Işıkay³

et al. 2020

Ann Clin Transl Neurol

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Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-proteincoupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T: p.Arg659Ter). Developmental delay, neonatal-or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late 610 childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Marafi

Mitani

Işıkay³

et al. 2020

Ann Clin Transl Neurol

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“…Gria1 is the hub gene in the Cortex‐Juvenile group, and it has been associated with ASD susceptibility. It encodes an AMPA receptor subunit and is essential for glutamatergic synaptic transmission [Salpietro et al, ]. For the Hip‐adult group, there are 12 hub genes identified, including Kdr , S1pr1 , Ubc , Grm2 , Grin2b , Nrxn1 , Pdyn , Grin3a , Itgam , Grin2a , Gabra2 , and Camk4 .…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

et al. 2019

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Genetic mutations are the major pathogenic factor of Autism Spectrum Disorder (ASD). In recent years, more and more ASD risk genes have been revealed, among which there are a group of transcriptional regulators. Considering the similarity of the core clinical phenotypes, it is possible that these different factors may regulate the expression levels of certain key targets. Identification of these targets could facilitate the understanding of the etiology and developing of novel diagnostic and therapeutic methods. Therefore, we performed integrated transcriptome analyses of RNA‐Seq and microarray data in multiple ASD mouse models and identified a number of common downstream genes in various brain regions, many of which are related to the structure and function of the synapse components or drug addiction. We then established protein–protein interaction networks of the overlapped targets and isolated the hub genes by 11 algorithms based on the topological structure of the networks, including Sdc4, Vegfa, and Cp in the Cortex‐Adult subgroup, Gria1 in the Cortex‐Juvenile subgroup, and Kdr, S1pr1, Ubc, Grm2, Grin2b, Nrxn1, Pdyn, Grin3a, Itgam, Grin2a, Gabra2, and Camk4 in the Hippocampus‐Adult subgroup, many of which have been associated with ASD in previous studies. Finally, we cross compared our results with human brain transcriptional data sets and verified several key candidates, which may play important role in the pathology process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRIN2A, GABRA2, and CAMK4. In summary, by integrated bioinformatics analysis, we have identified a series of potentially important molecules for future ASD research. Autism Res 2020, 13: 352–368. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Abnormal transcriptional regulation accounts for a significant portion of Autism Spectrum Disorder. In this study, we performed transcriptome analyses of mouse models to identify common downstream targets of transcriptional regulators involved in ASD. We identified several recurrent target genes that are close related to the common pathological process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRM2, NRXN1, GRIN3A, ITGAM, GRIN2A, GABRA2, and CAMK4. These results provide potentially important targets for understanding the molecular mechanism of ASD.

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Drug‐resistant epilepsy: Drug target hypothesis and beyond the receptors

Fonseca-Barriendos¹,

Frías‐Soria²,

Pérez-Pérez³

et al. 2021

Epilepsia Open

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Epilepsy is a common chronic neurological disorder that affects more than 50 million people worldwide. 1 Antiseizure drug that serves as the first line of treatment is used to control seizures. However, one-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE) because they fail to achieve control of seizures despite the appropriate treatment schemes used (in monotherapy or various combinations). 2 According to the target hypothesis that explains the drug-resistance phenotype in epilepsy, failure to control epileptic activity by antiseizure medication (ASM) results in losing therapeutic efficacy as a consequence of alterations in the structure and/or function of their targets 3 (Figure 1). In this regard, adopting different therapeutic targets in patients with DRE is crucial, which include alterations in voltage-gated sodium channels (VGSCs) and γ-aminobutyric acid (GABA) receptors.Some studies confirm that resected brain tissue obtained from patients with drug-resistant temporal lobe epilepsy (DR-TLE) who have undergone surgery show reduced sensitivity to carbamazepine, a drug that inhibits VGSC. 4,5 Experimental models have not yet reproduced this condition in DRE. However, studies in models of acute seizures and epilepsy have demonstrated induced alterations in VGSC similar to those detected in brain tissue of patients with the DRE. [6][7][8]

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AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Cited by 156 publications

References 65 publications

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

Drug‐resistant epilepsy: Drug target hypothesis and beyond the receptors

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