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

Abstract

Clustering of inhibitory gamma-aminobutyric acid(A) (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 GABA(A) receptor subtypes involved in epilepsy, anxiety, aggression, insomnia, and learning and memory.

• Authors: Vera M Kalscheuer, Luciana Musante, Cheng Fang, Kirsten Hoffmann, Celine Fuchs, Eloisa Carta, Emma Deas, Kanamarlapudi Venkateswarlu, Corinna Menzel, Reinhard Ullmann, Niels Tommerup, Leda Dalprà, Andreas Tzschach, Angelo Selicorni, Bernhard Lüscher, Hans-Hilger Ropers, Kirsten Harvey, Robert J Harvey
• Journal: Human mutation (Hum Mutat) Vol. 30 Issue 1 Pg. 61-8 (Jan 2009) ISSN: 1098-1004 [Electronic] United States
• PMID: 18615734 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2008 Wiley-Liss, Inc.

Chemical References

• ARHGEF9 protein, human
• Carrier Proteins
• Guanine Nucleotide Exchange Factors
• Membrane Proteins
• RNA, Messenger
• Receptors, GABA-A
• Receptors, Glycine
• Rho Guanine Nucleotide Exchange Factors
• gephyrin

Topics

• Adolescent
• Aggression
• Amino Acid Sequence
• Anxiety (genetics)
• Base Sequence
• Carrier Proteins (metabolism)
• Cells, Cultured
• Epilepsy (genetics)
• Female
• Guanine Nucleotide Exchange Factors (genetics)
• Humans
• Intellectual Disability (genetics)
• Membrane Proteins (metabolism)
• Molecular Sequence Data
• RNA, Messenger (metabolism)
• Receptors, GABA-A (metabolism)
• Receptors, Glycine (genetics, metabolism)
• Rho Guanine Nucleotide Exchange Factors
• Translocation, Genetic