A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation

V M Kalscheuer; L Musante; C Fang; K Hoffmann; C Fuchs; E Carta; E Deas; K Venkateswarlu; C Menzel; R Ullmann; N Tommerup; L Dalprà; A Tzschach; A Selicorni; B Lüscher; H H Ropers; K Harvey; Robert J Harvey

doi:10.1002/humu.20814

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A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation

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A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation

V M Kalscheuer, L Musante, C Fang, K Hoffmann, C Fuchs, E Carta, E Deas, K Venkateswarlu, C Menzel, R Ullmann, …

Human Mutation, Vol.30(1), pp.61-68

2009

DOI: https://doi.org/10.1002/humu.20814

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Abstract

GABAA receptors

glycine receptors

collybistin

ARHGEF9

gephyrin

clustering

anxiety

epilepsy

mental retardation

aggression

Clustering of inhibitory γ-aminobutyric acidA (GABA A) 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 GABA A 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. © 2008 Wiley-Liss, Inc.

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Title: A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation
Authors: V M Kalscheuer (Author) - Max Planck Institute for Molecular Genetics, Germany
L Musante (Author) - Max Planck Institute for Molecular Genetics, Germany
C Fang (Author) - Penn State University, United States
K Hoffmann (Author) - Max Planck Institute for Molecular Genetics, Germany
C Fuchs (Author) - University College London, United Kingdom
E Carta (Author) - University College London, United Kingdom
E Deas (Author) - University College London, United Kingdom
K Venkateswarlu (Author) - Swansea University, United Kingdom
C Menzel (Author) - Max Planck Institute for Molecular Genetics, Germany
R Ullmann (Author) - Max Planck Institute for Molecular Genetics, Germany
N Tommerup (Author) - Wilhelm Johannsen Centre for Functional Genome Research, Denmark
L Dalprà (Author) - University of Milan-Bicocca, Italy
A Tzschach (Author) - Max Planck Institute for Molecular Genetics, Germany
A Selicorni (Author) - Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico Foundation, Italy
B Lüscher (Author) - Penn State University, United States
H H Ropers (Author) - Max Planck Institute for Molecular Genetics, Germany
K Harvey (Author) - University College London, United Kingdom
Robert J Harvey (Author) - University College London, United Kingdom
Publication details: Human Mutation, Vol.30(1), pp.61-68
Publisher: John Wiley & Sons Inc.
Date published: 2009
DOI: 10.1002/humu.20814
ISSN: 1059-7794
Copyright note: Copyright © 2009 The Authors. This is the accepted version of the following article: Kalscheuer, V M; Musante, L; Fang, C; Hoffmann, K; Fuchs, C; Carta, E; Deas, E; Venkateswarlu, K; Menzel, C; Ullmann, R; Tommerup, N; Dalprà , L; Tzschach, A; Selicorni, A; Lüscher, B; Ropers, H H; Harvey, K; Harvey, Robert J (2009). A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation, Human Mutation, 30:1, 61-68, which has been published in final form at http://dx.doi.org/10.1002/humu.20814
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99450310202621
Output Type: Journal article

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