4.8 Article

Human ARHGEF9 intellectual disability syndrome is phenocopied by a mutation that disrupts collybistin binding to the GABAA receptor α2 subunit

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MOLECULAR PSYCHIATRY
卷 27, 期 3, 页码 1729-1741

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DOI: 10.1038/s41380-022-01468-z

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  1. NIH [1R15NS124008-01, 5R01MH118263-02]

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Intellectual disability (ID) is a common neurodevelopmental disorder caused by genetic mutations. Mutations in single genes, such as ARHGEF9, have been found to be causative in ID, along with symptoms like epilepsy, abnormal EEG activity, behavioral symptoms, and sleep disturbances. By manipulating a specific gene, researchers discovered that modulation of GABA receptors may be a potential target for treating ID syndrome.
Intellectual disability (ID) is a common neurodevelopmental disorder that can arise from genetic mutations ranging from trisomy to single nucleotide polymorphism. Mutations in a growing number of single genes have been identified as causative in ID, including ARHGEF9. Evaluation of 41 ARHGEF9 patient reports shows ubiquitous inclusion of ID, along with other frequently reported symptoms of epilepsy, abnormal baseline EEG activity, behavioral symptoms, and sleep disturbances. ARHGEF9 codes for the Cdc42 Guanine Nucleotide Exchange Factor 9 collybistin (Cb), a known regulator of inhibitory synapse function via direct interaction with the adhesion molecule neuroligin-2 and the alpha 2 subunit of GABA(A) receptors. We mutate the Cb binding motif within the large intracellular loop of alpha 2 replacing it with the binding motif for gephyrin from the alpha 1 subunit (Gabra2-1). The Gabra2-1 mutation causes a strong downregulation of Cb expression, particularly at cholecystokinin basket cell inhibitory synapses. Gabra2-1 mice have deficits in working and recognition memory, as well as hyperactivity, anxiety, and reduced social preference, recapitulating the frequently reported features of ARHGEF9 patients. Gabra2-1 mice also have spontaneous seizures during postnatal development which can lead to mortality, and baseline abnormalities in low-frequency wavelengths of the EEG. EEG abnormalities are vigilance state-specific and manifest as sleep disturbance including increased time in wake and a loss of free-running rhythmicity in the absence of light as zeitgeber. Gabra2-1 mice phenocopy multiple features of human ARHGEF9 mutation, and reveal alpha 2 subunit-containing GABA(A) receptors as a druggable target for treatment of this complex ID syndrome.

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