A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation.
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.
Kalscheuer
Vera M
VM
Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany. kalscheu@molgen.mpg.de
Musante
Luciana
L
Fang
Cheng
C
Hoffmann
Kirsten
K
Fuchs
Celine
C
Carta
Eloisa
E
Deas
Emma
E
Venkateswarlu
Kanamarlapudi
K
Menzel
Corinna
C
Ullmann
Reinhard
R
Tommerup
Niels
N
Dalprà
Leda
L
Tzschach
Andreas
A
Selicorni
Angelo
A
Lüscher
Bernhard
B
Ropers
Hans-Hilger
HH
Harvey
Kirsten
K
Harvey
Robert J
RJ
D000293:Adolescent; D000374:Aggression; D000595:Amino Acid Sequence; D001007:Anxiety / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D014178:Translocation, Genetic
C577410:ARHGEF9 protein, human; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D064067:Rho Guanine Nucleotide Exchange Factors; C073441:gephyrin