ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal

Abstract

We identified a female patient with mental retardation and sensory hyperarousal. She has a de novo paracentric inversion of one X chromosome with completely skewed inactivation of the normal X chromosome. We aimed to identify whether a single gene or gene region caused her cognitive and behavioural impairment and that of others. Fluorescent in situ hybridisation (FISH) showed that the centromeric breakpoint disrupts a single gene: ARHGEF9 (CDC42 guanine nucleotide exchange factor (GEF) 9). We also found that the levels of the ARHGEF9 transcript from the patient are 10-fold less than those found in control samples. ARHGEF9 encodes a RhoGEF family protein: collybistin (hPEM), which is highly expressed in the brain. Collybistin can regulate actin cytoskeletal dynamics and may also modulate GABAergic and glycinergic neurotransmission through binding of a scaffolding protein, gephyrin, at the synapse. This potential dual role may explain both the mental retardation and hyperarousal observed in our patient.

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

“…10,11,32,33 This hyperactivation of the mTORC1 pathway has been shown to stimulate excessive protein synthesis in neuronal cells, leading to disturbances in neuronal differentiation and morphology, synaptic connectivity, and plasticity. Loss-of-function variants in CB, which are known to reduce GABAergic transmission and alter synaptic plasticity, have been associated with overlapping phenotypes, that is, intellectual disability, epilepsy, anxiety, 15,[22][23][24][25] and now autism, present in the patient here described. Therefore, the data presented here point to the possibility that mTORC1 pathway overactivation in CB-deficient neuronal cells might also contribute to the cognitive and behavioral abnormalities in patients with loss-of-function variants in CB.…”

“…Consequently, dysregulation of mTORC1 activity might contribute to some of the neurological abnormalities observed in patients with CB variants, such as intellectual disability, epilepsy, and anxiety. 15,[22][23][24][25] However, to our knowledge, there are no published studies addressing these questions.…”

Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy

“…Consequently, the patients showed low expression of ARHGEF9 and suffered mild mental retardation and sensory hyperarousal, but no hyperekplexia. 17,18 Although these female patients with X chromosome imbalances are specific cases, these findings suggested that ARHGEF9 is related to various phenotypes and would be a candidate gene for XLMR associated with epilepsy. 17,18 Previously Marco et al 17 analyzed the nucleotide sequences of ARHGEF9 in 477 mentally retarded males, and there was no pathogenic mutation.…”

“…17,18 Generally, X chromosome inactivation is randomly observed. However, patients with balanced translocation involving X chromosome often show non-random inactivation in normal X chromosome.…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…ARHGEF9 was first identified in a yeast two hybrid screen as an interactor with the scaffolding protein gephyrin 267,268 ( Figure 6). ARHGEF9 contains a diffuse B-cell lymphoma (Dbl) homology (DH) domain that interacts with RhoGTPases, a PH domain and a SH3 domain 269 for ARHGEF9, associated with severe neurological traits and ASD [276][277][278] .…”