Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Stolz, Jacob R.; Foote, Kendall M.; Veenstra‐Knol, Hermine E.; Pfundt, Rolph; Broeke, Sanne W. ten; Leeuw, Nicole de; Roht, Laura; Pajusalu, Sander; Part, Reelika; Rebane, Ionella; Õunap, Katrin; Stark, Zornitza; Kirk, Edwin P.; Lawson, John A.; Lunke, Sebastian; Christodoulou, John; Louie, Raymond J.; Rogers, R. Curtis; Davis, Jessica; Innes, A. Micheil; Wei, Xing‐Chang; Keren, Boris; Mignot, Cyril; Lebel, Robert Roger; Sperber, Steven M.; Sakonju, Ai; Dosa, Nienke P.; Barge-Schaapveld, Daniela Q.C.M.; Peeters-Scholte, Cacha; Ruivenkamp, Claudia; Bon, Bregje W.M. van; Kennedy, Joanna; Low, Karen; Ellard, Sian; Pang, Lewis; Junewick, Joseph; Mark, Paul R.; Carvill, Gemma L.; Swanson, Geoffrey T.

doi:10.1016/j.ajhg.2021.07.007

Cited by 26 publications

(20 citation statements)

References 62 publications

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“…Outside of RSFA, we found a single locus on chromosome 6 harbouring GRIK2 that was associated with local efficiency. GRIK2 affects kainite, a neuroexcitatory amino acid agonist that activates glutamate receptors, and has been demonstrated to be important for synaptic transmission 42 as well as having been implicated in a number of neurological conditions 43 . KCND2 was identified in our GWAS of the subcortical-cerebellum network, it is a voltage-gated potassium channel gene known to associate with rare neurological conditions such as early myoclonic encephalopathy and developmental and epileptic encephalopathy 3.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of the human brain functional connectome reveals strong vascular component underlying global network efficiency

Bell

Tozer

Markus

2022

Sci Rep

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Complex brain networks play a central role in integrating activity across the human brain, and such networks can be identified in the absence of any external stimulus. We performed 10 genome-wide association studies of resting state network measures of intrinsic brain activity in up to 36,150 participants of European ancestry in the UK Biobank. We found that the heritability of global network efficiency was largely explained by blood oxygen level-dependent (BOLD) resting state fluctuation amplitudes (RSFA), which are thought to reflect the vascular component of the BOLD signal. RSFA itself had a significant genetic component and we identified 24 genomic loci associated with RSFA, 157 genes whose predicted expression correlated with it, and 3 proteins in the dorsolateral prefrontal cortex and 4 in plasma. We observed correlations with cardiovascular traits, and single-cell RNA specificity analyses revealed enrichment of vascular related cells. Our analyses also revealed a potential role of lipid transport, store-operated calcium channel activity, and inositol 1,4,5-trisphosphate binding in resting-state BOLD fluctuations. We conclude that that the heritability of global network efficiency is largely explained by the vascular component of the BOLD response as ascertained by RSFA, which itself has a significant genetic component.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study of the human brain functional connectome reveals strong vascular component underlying global network efficiency

Bell

Tozer

Markus

2022

Sci Rep

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“…GluK1 and GluK2 subunits play a role in presence of the apparent unitary conductance of kainate-type channels in developing granule cells [ 85 ], indicating the role of KAR subunits in immature granule cells at the early stage of cerebellar development. A recent case report has shown that missense variants of the GRIK2 gene, which encodes GluK2 protein, give rise to neurodevelopmental disorder of diverse phenotype including cerebellar atrophy at an individual of about three years of age, suggesting a critical importance of KAR function during early development of the cerebellum [ 86 ]. Indeed, the predominance of GluK2 and GluK5 throughout the developmental period suggests that KAR subunits may be essential for cerebellar development [ 82 ].…”

Section: Roles Of Kars In Cerebellum Enlightening Cerebellum-like Dcnmentioning

confidence: 99%

Focusing on the Emerging Role of Kainate Receptors in the Dorsal Cochlear Nucleus (DCN) and Cerebellum

Tang²

2023

IJMS

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Mammals have a dorsal cochlear nucleus (DCN), which is thought to be a cerebellum-like structure with similar features in terms of structure and microcircuitry to the cerebellum. Both the DCN and cerebellum perform their functions depending on synaptic and neuronal networks mediated by various glutamate receptors. Kainate receptors (KARs) are one class of the glutamate receptor family and are strongly expressed in the hippocampus, the cerebellum, and cerebellum-like structures. The cellular distribution and the potential role of KARs in the hippocampus have been extensively investigated. However, the cellular distribution and the potential role of KARs in cerebellum-like structures, including the DCN and cerebellum, are poorly understood. In this review, we summarize the similarity between the DCN and cerebellum at the levels of structure, circuitry, and cell type as well as the investigations referring to the expression patterns of KARs in the DCN and cerebellum according to previous studies. Recent studies on the role of KARs have shown that KARs mediate a bidirectional modulatory effect at parallel fiber (PF)–Purkinje cell (PC) synapses in the cerebellum, implying insights into their roles in cerebellum-like structures, including the DCN, that remain to be explored in the coming years.

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“…In addition, mutations on the gene GRIA2 , referent to the GluA2 subunit, are also well described as an important factor for epilepsy and other pathologies regarding the functioning of AMPA receptors (Salpietro et al, 2019). Additionally, mutations on the GRIK2 gene, responsible for the GluK2 subunit in kainate receptors, were recently proposed to have some association with epilepsy as well (Stolz et al, 2021).…”

Section: Innovative Therapeutic Options For Epilepsymentioning

confidence: 99%

Innovative treatments for epilepsy: Venom peptides, cannabinoids, and neurostimulation

Lima

Loyola

Bicca

et al. 2022

J of Neuroscience Research

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Antiepileptic drugs have been successfully treating epilepsy and providing individuals sustained seizure freedom. However, about 30% of the patients with epilepsy present drug resistance, which means they are not responsive to the pharmacological treatment. Considering this, it becomes extremely relevant to pursue alternative therapeutic approaches, in order to provide appropriate treatment for those patients and also improve their quality of life. In the light of that, this review aims to discuss some innovative options for the treatment of epilepsy, which are currently under investigation, addressing strategies that go from therapeutic compounds to clinical procedures. For instance, peptides derived from animal venoms, such as wasps, spiders, and scorpions, demonstrate to be promising antiepileptic molecules, acting on a variety of targets. Other options are cannabinoids and compounds that modulate the endocannabinoid system, since it is now known that this network is involved in the pathophysiology of epilepsy. Furthermore, neurostimulation is another strategy, being an alternative clinical procedure for drug‐resistant patients who are not eligible for palliative surgeries.

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Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Cited by 26 publications

References 62 publications

Genome-wide association study of the human brain functional connectome reveals strong vascular component underlying global network efficiency

Genome-wide association study of the human brain functional connectome reveals strong vascular component underlying global network efficiency

Focusing on the Emerging Role of Kainate Receptors in the Dorsal Cochlear Nucleus (DCN) and Cerebellum

Innovative treatments for epilepsy: Venom peptides, cannabinoids, and neurostimulation

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