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

Kalscheuer, V. M., Musante, L., Fang, C., Hoffmann, K., Fuchs, C., Carta, E., et al. (2009). A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. Human Mutation, 30(1), 61-68. doi:10.1002/humu.20814.

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Genre: Journal Article
Alternative Title : Hum Mutat

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 Creators:
Kalscheuer, Vera M.1, Author           
Musante, Luciana2, Author           
Fang, Cheng, Author
Hoffmann, Kirsten3, Author
Fuchs, Celine, Author
Carta, Eloisa, Author
Deas, Emma, Author
Venkateswarlu, Kanamarlapudi, Author
Menzel, Corinna3, Author
Ullmann, Reinhard4, Author           
Tommerup, Niels, Author
Dalprà, Leda, Author
Tzschach, Andreas5, Author           
Selicorni, Angelo, Author
Lüscher, Bernhard, Author
Ropers, Hans-Hilger5, Author           
Harvey, Kirsten, Author
Harvey, Robert J., Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              
2Familial Cognitive Disorders (Luciana Musante), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479644              
3Max Planck Society, ou_persistent13              
4Molecular Cytogenetics (Reinhard Ullmann), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479645              
5Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              

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Free keywords: GABAA receptors; Glycine receptors; Collybistin; ARHGEF9; Gephyrin; Clustering; Anxiety; Epilepsy; Mental retardation; Aggression
 Abstract: Clustering of inhibitory -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.

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Language(s): eng - English
 Dates: 2009-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
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Title: Human Mutation
  Alternative Title : Hum Mutat
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 30 (1) Sequence Number: - Start / End Page: 61 - 68 Identifier: ISSN: 1059-7794