A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration.
A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration.
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DOI：
10.1007/s10048-015-0446-0
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发表时间：
2015-07
期刊：
影响因子：
2.2
通讯作者：
Elpeleg O
中科院分区：
文献类型：
--
作者：
Damseh N;Danson CM;Al-Ashhab M;Abu-Libdeh B;Gallon M;Sharma K;Yaacov B;Coulthard E;Caldwell MA;Edvardson S;Cullen PJ;Elpeleg O
神经细胞表面的组成决定了突触的可塑性，从而决定了认知的发展。突触的这种重塑是由内吞细胞网络控制的，内化跨膜蛋白，然后将它们分类回到细胞表面或将它们带到溶酶体进行降解。多蛋白逆转聚体复合体是这一选择的核心，它捕获特定的跨膜蛋白并重塑细胞膜，形成孤立的货物浓缩运输载体。我们调查了一个血缘关系密切的家庭，有四名患者，他们在婴儿期表现为顽固性肌阵挛癫痫和缺乏精神运动发育。利用外显子分析，我们在SNX27中发现了一个纯合子的有害突变，它编码了一个逆转录的货物适配器分选Nexin 27。在对患者成纤维细胞的Western分析中，与对照样本相比，编码的突变蛋白的表达水平是不可检测的。患者的表现和临床病程总结了SNX27基因敲除小鼠的报告。由于SNX27介导的分选的货物蛋白包括离子型谷氨酸受体亚基，并且在SNX27−/−神经元中AMPA受体的内体-细胞表面突触插入受到严重干扰，因此推测患者中观察到的神经功能异常至少部分归因于离子型谷氨酸受体的缺陷分选。SNX27缺乏症现在被添加到与逆转录功能障碍相关的神经退行性疾病的日益增长的名单中。
The composition of the neuronal cell surface dictates synaptic plasticity and thereby cognitive development. This remodeling of the synapses is governed by the endocytic network which internalize transmembrane proteins, then sort them back to the cell surface or carry them to the lysosome for degradation. The multi-protein retromer complex is central to this selection, capturing specific transmembrane proteins and remodeling the cell membrane to form isolated cargo-enriched transport carriers. We investigated a consanguineous family with four patients who presented in infancy with intractable myoclonic epilepsy and lack of psychomotor development. Using exome analysis, we identified a homozygous deleterious mutation in SNX27, which encodes sorting nexin 27, a retromer cargo adaptor. In western analysis of patient fibroblasts, the encoded mutant protein was expressed at an undetectable level when compared with a control sample. The patients’ presentation and clinical course recapitulate that reported for the SNX27 knock-out mouse. Since the cargo proteins for SNX27-mediated sorting include subunits of ionotropic glutamate receptors and endosome-to-cell surface synaptic insertion of AMPA receptors is severely perturbed in SNX27−/− neurons, it is proposed that at least part of the neurological aberrations observed in the patients is attributed to defective sorting of ionotropic glutamate receptors. SNX27 deficiency is now added to the growing list of neurodegenerative disorders associated with retromer dysfunction.