ArticleHuman molecular genetics2017
A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 48 citations in OpenAlex.
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- Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes.Brain : a journal of neurology · 2024Article
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- A Pathogenic Missense Mutation in Kainate Receptors Elevates Dendritic Excitability and Synaptic Integration through Dysregulation of SK Channels.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Clinical and functional consequences of GRIA variants in patients with neurological diseases.Cellular and molecular life sciences : CMLS · 2023Article
- CRISPR/Cas-Based Approaches to Study Schizophrenia and Other Neurodevelopmental Disorders.International journal of molecular sciences · 2022Review
- Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome.American journal of human genetics · 2022Article
- Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant.Human genetics · 2022Article
- Myoclonic status epilepticus and cerebellar hypoplasia associated with a novel variant in the GRIA3 gene.Neurogenetics · 2022Article
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.American journal of human genetics · 2021Article
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Authors and funding
28 authors at 9 institutions in 2 countries.
Funding
Abstract
The discovery of genetic variants influencing sleep patterns can shed light on the physiological processes underlying sleep. As part of a large clinical sequencing project, WGS500, we sequenced a family in which the two male children had severe developmental delay and a dramatically disturbed sleep-wake cycle, with very long wake and sleep durations, reaching up to 106-h awake and 48-h asleep. The most likely causal variant identified was a novel missense variant in the X-linked GRIA3 gene, which has been implicated in intellectual disability. GRIA3 encodes GluA3, a subunit of AMPA-type ionotropic glutamate receptors (AMPARs). The mutation (A653T) falls within the highly conserved transmembrane domain of the ion channel gate, immediately adjacent to the analogous residue in the Grid2 (glutamate receptor) gene, which is mutated in the mouse neurobehavioral mutant, Lurcher. In vitro, the GRIA3(A653T) mutation stabilizes the channel in a closed conformation, in contrast to Lurcher. We introduced the orthologous mutation into a mouse strain by CRISPR-Cas9 mutagenesis and found that hemizygous mutants displayed significant differences in the structure of their activity and sleep compared to wild-type littermates. Typically, mice are polyphasic, exhibiting multiple sleep bouts of sleep several minutes long within a 24-h period. The Gria3A653T mouse showed significantly fewer brief bouts of activity and sleep than the wild-types. Furthermore, Gria3A653T mice showed enhanced period lengthening under constant light compared to wild-type mice, suggesting an increased sensitivity to light. Our results suggest a role for GluA3 channel activity in the regulation of sleep behavior in both mice and humans.
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