A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability
Open accessAbstract
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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A point mutation in the AMPAR subunit GluA3 causes circadian rhythm disruption and intellectual disability.
“Such an interaction is worth investigation, as a reported point mutation in the AMPAR subunit GluA3 was shown to cause circadian rhythm disruption and intellectual disability (125).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [125]
The Introduction reports a GRIA3 mutation, which affects the GluA3 subunit, in patients with profound intellectual disability and severely disrupted sleep–wake cycles. But the Results say the authors could not determine whether the sleep disturbance arose from the circadian system, and the Discussion suggests it may instead affect sleep–wake organization. Calling it a demonstrated cause of circadian rhythm disruption overstates the finding. (LLM, conf=0.90)
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- Authors
- Davies, B., Brown, L. A., Cais, O., Watson, J., Clayton, A. J., Chang, V. T., Biggs, D., Preece, C., Hernandez-Pliego, P., Krohn, J., Bhomra, A., Twigg, S. R. F., Rimmer, A., Kanapin, A., The WGS500 Consortium, Sen, A., Zaiwalla, Z., McVean, G., Foster, R., Donnelly, P., Taylor, J. C., Blair, E., Nutt, D., Aricescu, A. R., Greger, I. H., Peirson, S. N., Flint, J., & Martin, H. C.
- Affiliations
- Centre for Human Genetics (GB)
- University of Oxford (GB)
- Medical Research Council (MRC) Laboratory of Molecular Biology, Neurobiology Division, Cambridge, Cambridgeshire CB2 0QH, UK
- MRC Laboratory of Molecular Biology (GB)
- Institute of Cancer Research (GB)
- John Radcliffe Hospital (GB)
- Nuffield Department of Clinical Neurosciences, Sleep and Circadian Neuroscience Institute, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK
- Oxford University Hospitals NHS Trust (GB)
- Imperial College London (GB)
- Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California-Los Angeles, CA 90095, USA
- Wellcome Sanger Institute (GB)
- Corresponding author
- Martin, Hilary C
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-07-14
- Volume
- 26
- Issue
- 20
- Pages
- 3869-3882
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC5639461
- OpenAlex
- W2767002065
- Cited by
- 48
- References
- 67
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 6 · 2018: 1
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Human Molecular Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (090532/Z/09/Z, 093329, 098461)
- Medical Research Council (MC_UP_1201/15 and L009609 to A.R.A.; MC_U105174197 to J.F.W., O.C. and I.H.G.)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- GRIA3, GluA3, AMPA receptors, X-linked intellectual disability, developmental delay, sleep-wake cycle, sleep architecture, polyphasic sleep, circadian period, photosensitivity, GRID2, channel gating, CRISPR/Cas9 mouse model
- MeSH terms
- Adult, Amino Acid Sequence, Animals, Base Sequence, Disease Models, Animal, Humans, Male, Intellectual Disability, Mice, Inbred C57BL, Sleep Wake Disorders, Point Mutation, Receptors, AMPA, Mice
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