ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal
ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal
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DOI：
10.1136/jmg.2007.052324
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发表时间：
2008-02-01
影响因子：
4
通讯作者：
Sherr, E. H.
中科院分区：
文献类型：
--
作者：
Marco, E. J.;Abidi, F. E.;Sherr, E. H.
引言：我们发现一名女性患者患有精神发育迟滞和感觉过度觉醒。她有一个从头的染色体倒位的一个正常的X染色体完全歪斜失活的X chromosome.Objective：我们的目的是确定是否是一个单一的基因或基因区域造成她的认知和行为impairment.Results：荧光原位杂交（FISH）显示，着丝粒断点破坏一个单一的基因：ARHGEF 9（CDC 42鸟嘌呤核苷酸交换因子（GEF）9）。端粒断裂位于基因贫乏区。我们还发现，患者的ARHGEF 9转录物水平比对照样本中的水平低10倍。因此，我们测序的编码外显子和内含子/外显子边界的ARHGEF 9基因在99个先证者的家庭与X连锁精神发育迟滞（XLMR）和477智力迟钝的男性，其中诊断脆性X综合征已被排除。我们没有发现任何致病性变化，但是，我们确定内含子核苷酸的变化，可能会改变splicing.Conclusion：ARHGEF 9编码的RhoGEF家族蛋白：collybistin（hPEM），这是高度表达的发展和成人大脑。Collybistin可以调节肌动蛋白细胞骨架动力学，并且还可以通过在突触处结合支架蛋白（桥蛋白）来调节GABA能和甘氨酸能神经传递。这种潜在的双重作用可以解释在我们的病人中观察到的精神发育迟滞和过度觉醒。虽然ARHGEF 9似乎是男性精神发育迟滞的一种罕见原因，但在精神发育迟滞和感觉过度觉醒患者中应予以考虑。
Introduction: We identified a female patient with mental retardation and sensory hyperarousal. She has a de novo paracentric inversion of one X chromosome with completely skewed inactivation of the normal X chromosome.Objective: We aimed to identify whether a single gene or gene region caused her cognitive and behavioural impairment and that of others.Results: Fluorescent in situ hybridisation (FISH) showed that the centromeric breakpoint disrupts a single gene: ARHGEF9 (CDC42 guanine nucleotide exchange factor (GEF) 9). The telomeric break lies in a gene poor region. We also found that the levels of the ARHGEF9 transcript from the patient are 10-fold less than those found in control samples. Consequently, we sequenced the coding exons and intron/exon borders of the ARHGEF9 gene in 99 probands from families with X linked mental retardation (XLMR) and 477 mentally retarded males in whom a diagnosis of Fragile X syndrome had been excluded. We did not identify any pathogenic changes; however, we did identify intronic nucleotide changes that might alter splicing.Conclusion: ARHGEF9 encodes a RhoGEF family protein: collybistin (hPEM), which is highly expressed in the developing and adult brain. Collybistin can regulate actin cytoskeletal dynamics and may also modulate GABAergic and glycinergic neurotransmission through binding of a scaffolding protein, gephyrin, at the synapse. This potential dual role may explain both the mental retardation and hyperarousal observed in our patient. While ARHGEF9 appears to be an uncommon cause of mental retardation in males, it should be considered in patients with mental retardation and sensory hyperarousal.