A balanced chromosomal translocation disruptingARHGEF9is associated with epilepsy, anxiety, aggression, and mental retardation

Abstract

Clustering of inhibitory γ-aminobutyric acidA (GABAA) and glycine receptors at synapses is thought to involve key interactions between the receptors, a “scaffolding” protein known as gephyrin and the RhoGEF collybistin. We report the identification of a balanced chromosomal translocation in a female patient presenting with a disturbed sleep-wake cycle, late-onset epileptic seizures, increased anxiety, aggressive behavior, and mental retardation, but not hyperekplexia. Fine mapping of the breakpoint indicates disruption of the collybistin gene (ARHGEF9) on chromosome Xq11, while the other breakpoint lies in a region of 18q11 that lacks any known or predicted genes. We show that defective collybistin transcripts are synthesized and exons 7–10 are replaced by cryptic exons from chromosomes X and 18. These mRNAs no longer encode the pleckstrin homology (PH) domain of collybistin, which we now show binds phosphatidylinositol-3-phosphate (PI3P/ PtdIns-3-P), a phosphoinositide with an emerging role in membrane trafficking and signal transduction, rather than phosphatidylinositol 3,4,5-trisphosphate (PIP3/PtdIns-3,4,5-P) as previously suggested in the “membrane activation model” of gephyrin clustering. Consistent with this finding, expression of truncated collybistin proteins in cultured neurons interferes with synaptic localization of endogenous gephyrin and GABAA receptors. These results suggest that collybistin has a key role in membrane trafficking of gephyrin and selected GABAA receptor subtypes involved in epilepsy, anxiety, aggression, insomnia, and learning and memory.

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.…”

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] .…”

Molecular and functional heterogeneity of GABAergic synapses

“…The significance of CB for glycinergic and GABAergic synaptic function is underscored by the discovery of several loss of function mutations in ARGEF9 underlying severe forms of X-linked mental retardation and hyperekpleksia [42,43]. In recombinant expression systems, CB is essential for cell-surface translocation of gephyrin [44].…”