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

Tokyo Women's Medical University Institute for Integrated Medical Sciences, 8-1 Kawada-cho, Shinjuku, Tokyo, Japan.
Journal of Human Genetics (Impact Factor: 2.46). 06/2011; 56(8):561-5. DOI: 10.1038/jhg.2011.58
Source: PubMed


Microarray-based comparative genomic hybridization analysis identified a 737-kb microdeletion of Xq11.1, including the cell division cycle 42 guanine nucleotide exchange factor (GEF)-9 gene (ARHGEF9), encoding collybistin, which has a pivotal role in formation of postsynaptic glycine and γ-aminobutyric acid receptor clusters, in a male patient with severe mental retardation and epilepsy. No overlapping deletion with this was identified in the database of genomic copy number variations. A cohort study of ARHGEF9 nucleotide sequence identified a nonsense mutation in another male patient with severe mental retardation and epilepsy. This mutation affects one of the three transcript variants of ARHGEF9, which was confirmed to be expressed in the brain by reverse transcription-PCR. Although this nonsense mutation was shared with the patient's mother, it was not observed in 100 normal individuals. Both male patients suffered epileptic seizures after 1 year of age. Brain magnetic resonance imaging revealed mild frontal atrophy in the first patient and right frontal polymicrogyria in the second patient. Three previously reported mutations of ARHGEF9 consisted of a missense mutation in a male patient with hyperekplexia and two chromosomal disruptions in two female patients. The common phenotypic effects of all ARHGEF9 mutations were mental retardation and epilepsy. Therefore, ARHGEF9 is likely to be responsible for syndromic X-linked mental retardation associated with epilepsy.

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    • "By contrast,Shimojima et al. (2011)identified an ARHGEF9 nonsense mutation (p.Q2X) in an individual with refractory seizures, right frontal polymicrogyria and severe psychomotor retardation.Lemke et al. (2012)also reported a p.R290H missense mutation in the CB RhoGEF domain associated with epilepsy and ID. Furthermore, large de novo deletions affecting ARHGEF9 as well as neighboring genes SPIN4 and LOC92249 have been reported to be associated with complex phenotypes that include features such as partial seizures, delayed psychomotor development and generalized overgrowth (Table 1;Lesca et al., 2011;Shimojima et al., 2011). Lastly, a balanced chromosomal translocation (Kalscheuer et al., 2009) and a paracentric inversion (Marco et al., 2008) have been reported with yet more clinical features, including disturbed sleep-wake cycle, increased anxiety and aggressive behavior or hyperarousal, respectively.t(Xq11.1;18q11.21) "
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    ABSTRACT: Non-syndromal X-linked intellectual disability (NS-XLID) represents a broad group of clinical disorders in which ID is the only clinically consistent manifestation. Although in many cases either chromosomal linkage data or knowledge of the >100 existing XLID genes has assisted mutation discovery, the underlying cause of disease remains unresolved in many families. We report the resolution of a large family (K8010) with NS-XLID, with variable macrocephaly and macro-orchidism. Although a previous linkage study had mapped the locus to Xq12-q21, this region contained too many candidate genes to be analyzed using conventional approaches. However, X-chromosome exome sequencing, bioinformatics analysis and segregation analysis revealed a novel missense mutation (c.1012C>T; p.R338W) in ARHGEF9. This gene encodes collybistin, a neuronal GDP-GTP exchange factor previously implicated in several cases of XLID, as well as clustering of gephyrin and GABAA receptors at inhibitory synapses. Molecular modeling of the collybistin R338W substitution revealed that this change results in the substitution of a long electropositive side-chain with a large non-charged hydrophobic side-chain. The R338W change is predicted to result in clashes with adjacent amino acids (K363 and D335) and disruption of electrostatic potential and local folding of the PH domain, which is known to bind phosphatidylinositol-3-phosphate (PI3P/PtdIns-3-P). Consistent with this finding, functional assays revealed that recombinant collybistin CB2SH3-R338W was deficient in PI3P binding and was not able to translocate EGFP-gephyrin to submembrane microaggregates in an in vitro clustering assay. Taken together, these results suggest that the R338W mutation in ARHGEF9 is the underlying cause of NS-XLID in this family.
    Preview · Article · Jan 2016 · Frontiers in Molecular Neuroscience
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    • "On the other hand, it should be noted that mutations in ARHGEF9, encoding collybistin and GPHN, encoding gephyrin, are not commonly associated with hyperekplexia. Rather, mutations in ARHGEF9 were reported to cause X-linked intellectual disability [13-16] whilst mutations in GPNH are associated with molybdenum co-factor deficiency [17,18]. "
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    ABSTRACT: Background Hyperekplexia (HPX) is a rare non-epileptic disorder manifesting immediately after birth with exaggerated persistent startle reaction to unexpected auditory, somatosensory and visual stimuli, and non-habituating generalized flexor spasm in response to tapping of the nasal bridge (glabellar tap) which forms its clinical hallmark. The course of the disease is usually benign with spontaneous amelioration with age. The disorder results from aberrant glycinergic neurotransmission, and several mutations were reported in the genes encoding glycine receptor (GlyR) α1 and β subunits, glycine transporter GlyT2 as well as two other proteins involved in glycinergic neurotransmission gephyrin and collybistin. Methods The phenotype of six newborns, belonging to Saudi Arabian kindred with close consanguineous marriages, who presented with hyperekplexia associated with severe brain malformation, is described. DNA samples were available from two patients, and homozygosity scan to determine overlap with known hyperkplexia genes was performed. Results The kindred consisted of two brothers married to their cousin sisters, each with three affected children who presented antenatally with excessive fetal movements. Postnatally, they were found to have microcephaly, severe hyperekplexia and gross brain malformation characterized by severe simplified gyral pattern and cerebellar underdevelopment. The EEG was normal and they responded to clonazepam. All of the six patients died within six weeks. Laboratory investigations, including metabolic screen, were unremarkable. None of the known hyperkplexia genes were present within the overlapping regions of homozygosity between the two patients for whom DNA samples were available. Conclusions We present these cases as a novel syndrome of lethal familial autosomal recessive hyperekplexia associated with microcephaly and severe brain malformation.
    Full-text · Article · Oct 2012 · BMC Neurology
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    • "The role of collybistin as a cofactor in gephyrin clustering is emphasized by human disease states, where mutations of collybistin result in X-linked mental retardation associated with epilepsy due to impaired GABAAR clustering (Shimojima et al., 2011). Mutations in the human CB gene (ARHGEF9 on Xq11.1) were found in patients with diverse neurological abnormalities, including hyperekplexia, epilepsy, insomnia, aggressive behavior, and anxiety (Kalscheuer et al., 2009). "
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    ABSTRACT: GABA(A) receptors are clustered at synaptic sites to achieve a high density of postsynaptic receptors opposite the input axonal terminals. This allows for an efficient propagation of GABA mediated signals, which mostly result in neuronal inhibition. A key organizer for inhibitory synaptic receptors is the 93 kDa protein gephyrin that forms oligomeric superstructures beneath the synaptic area. Gephyrin has long been known to be directly associated with glycine receptor β subunits that mediate synaptic inhibition in the spinal cord. Recently, synaptic GABA(A) receptors have also been shown to directly interact with gephyrin and interaction sites have been identified and mapped within the intracellular loops of the GABA(A) receptor α1, α2, and α3 subunits. Gephyrin-binding to GABA(A) receptors seems to be at least one order of magnitude weaker than to glycine receptors (GlyRs) and most probably is regulated by phosphorylation. Gephyrin not only has a structural function at synaptic sites, but also plays a crucial role in synaptic dynamics and is a platform for multiple protein-protein interactions, bringing receptors, cytoskeletal proteins and downstream signaling proteins into close spatial proximity.
    Full-text · Article · May 2012 · Frontiers in Cellular Neuroscience
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