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Hum Mol Genet. 2017 Oct 15;26(20):3869-3882. doi: 10.1093/hmg/ddx270.

A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability.

Author information

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire OX3 7BN, UK.
Nuffield Department of Clinical Neurosciences, Sleep and Circadian Neuroscience Institute, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK.
Medical Research Council (MRC) Laboratory of Molecular Biology, Neurobiology Division, Cambridge, Cambridgeshire CB2 0QH, UK.
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, Oxfordshire OX3 9DS, UK.
Institute for Cancer Research, London SM2 5NG, UK.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire OX3 7BN, UK.
Department of Oncology, University of Oxford, Oxford, Oxfordshire OX3 7DQ, UK.
Oxford Epilepsy Research Group, NIHR Biomedical Research Centre, Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Department of Neuroscience, John Radcliffe Hospital, Oxford, Oxfordshire OX3 9DU, UK.
Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, Oxfordshire OX3 7FZ, UK.
Department of Statistics, University of Oxford, Oxford, Oxfordshire OX1 3LB, UK.
National Institute for Health Research Oxford Biomedical Research Centre (NIHR Oxford BRC), Oxford, Oxfordshire OX3 7LE, UK.
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, Oxfordshire OX3 7HE, UK.
Division of Brain Sciences, Department of Medicine, Centre for Neuropsychopharmacology, Imperial College London, London W12 0NN, UK.
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California-Los Angeles, CA 90095, USA.
Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.


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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