A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation.
A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation.
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DOI：
10.1002/humu.20814
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发表时间：
2009-01
期刊：
影响因子：
3.9
通讯作者：
Harvey, Robert J.
中科院分区：
文献类型：
--
作者：
Kalscheuer, Vera M.;Musante, Luciana;Fang, Cheng;Hoffmann, Kirsten;Fuchs, Celine;Carta, Eloisa;Deas, Emma;Venkateswarlu, Kanamarlapudi;Menzel, Corinna;Ullmann, Reinhard;Tommerup, Niels;Dalpra, Leda;Tzschach, Andreas;Selicorni, Angelo;Luescher, Bernhard;Ropers, Hans-Hilger;Harvey, Kirsten;Harvey, Robert J.
关键词：
抑制性γ-氨基丁酸A（GABAA）和甘氨酸受体在突触处的聚集被认为涉及受体之间的关键相互作用，一种称为桥蛋白的“支架”蛋白和RhoGEF collybistin。我们报告了一个平衡染色体易位的女性患者，表现为睡眠-觉醒周期紊乱，迟发性癫痫发作，焦虑增加，攻击行为，精神发育迟滞，但不是hyperkplexia。断裂点的精细定位表明染色体Xq 11上的collybistin基因（ARHGEF 9）被破坏，而另一个断裂点位于18 q11的区域，该区域缺乏任何已知或预测的基因。我们发现，有缺陷的collybistin成绩单合成和外显子7-10被替换为神秘的外显子从染色体X和18。这些mRNA不再编码collybistin的pleckstrin同源（PH）结构域，我们现在显示其结合磷脂酰肌醇-3-磷酸（PI 3 P/ PtdIns-3-P），这是一种在膜运输和信号转导中具有新兴作用的磷酸肌醇，而不是如先前在桥蛋白聚集的“膜活化模型”中所建议的磷脂酰肌醇3，4，5-三磷酸（PIP 3/PtdIns-3，4，5-P）。与这一发现相一致的是，在培养的神经元中截短的collybistin蛋白的表达干扰内源性桥蛋白和GABAA受体的突触定位。这些结果表明，collybistin具有关键作用的膜运输的桥蛋白和选定的GABAA受体亚型参与癫痫，焦虑，侵略，失眠，学习和记忆。
Clustering of inhibitory γ-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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影响因子：
25
作者：
Essrich, C;Lorez, M;Lüscher, B
通讯作者：
Lüscher, B
影响因子：
3.5
作者：
Schweizer, C;Balsiger, S;Lüscher, B
通讯作者：
Lüscher, B
影响因子：
30.8
作者：
通讯作者：
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影响因子：
30.8
作者：
SHIANG, R;RYAN, SG;WASMUTH, JJ
通讯作者：
WASMUTH, JJ
影响因子：
4
作者：
Marco, E. J.;Abidi, F. E.;Sherr, E. H.
通讯作者：
Sherr, E. H.