Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients
Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients
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DOI：
10.1136/jmedgenet-2015-103239
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发表时间：
2015-11-01
影响因子：
4
通讯作者：
Elpeleg, Orly
中科院分区：
文献类型：
--
作者：
Edvardson, Shimon;Gerhard, Frank;Elpeleg, Orly
背景发育迟缓和认知障碍的遗传异质性是巨大的。内吞网络通过调节许多跨膜蛋白的分选，对神经发育和突触可塑性至关重要。该通路的中断可导致神经元病理学。内体生物发生依赖于两种Rab蛋白，Rab 5和Rab 7，其结合两种六聚体拴系复合物，内体C类核心液泡/内体拴系复合物（CORVET）和晚期内体/溶酶体同型融合和蛋白分选复合物（HOPS）。两种复合物均由四种核心蛋白组成，不同之处在于它们的特异性Rab-binding蛋白。目的确定神经系统疾病的分子基础，该疾病包括3- 8个月的全面发育停滞，增加的无脑痉挛，躯干张力减退和获得性小头畸形，伴有可变的癫痫发作障碍，伴有胼胝体变薄，在来自4个不相关的Ashkenazi-Jewish（AJ）家族的8名患者中，发现白色物质缺乏和髓鞘形成延迟。方法外显子组分析、纯合性作图和突变酵母中Mup 1-GFP转运测定。结果错义突变p.Cys846 Gly的纯合性，在所有患者中鉴定出了一种内体生物发生核心蛋白VPS 11。这被证明是一个创始人突变，携带者频率为0.6%的AJ人口。同源酵母突变体有中度损害的融合晚期内体的液泡在Mup 1-GFP transport assay.Conclusions我们推测，在神经元细胞中，损害的融合晚期内体的液泡将减弱质膜受体的降解，从而在我们的患者进行性神经元表型。应将VPS 11 p.Cys846Gly突变添加到AJ携带者筛查组中。
Background The genetic heterogeneity of developmental delay and cognitive impairment is vast. The endocytic network is essential for neural development and synaptic plasticity by regulating the sorting of numerous transmembrane proteins. Disruption of the pathway can lead to neuronal pathology. Endosomal biogenesis relies on two Rab proteins, Rab5 and Rab7, which bind to two hexameric tethering complexes, the endosomal class C core vacuole/endosome tethering complex (CORVET) and the late endosomal/lysosomal homotypic fusion and protein sorting complex (HOPS). Both complexes consist of four core proteins and differ by their specific Rab-binding proteins.Objectives To identify the molecular basis of a neurological disease, which consists of global developmental stagnation at 3-8months, increasing appendicular spasticity, truncal hypotonia and acquired microcephaly, with variable seizure disorder, accompanied by thin corpus callosum, paucity of white matter and delayed myelination in eight patients from four unrelated Ashkenazi-Jewish (AJ) families.Methods Exome analysis, homozygosity mapping and Mup1-GFP transport assay in mutant yeast.Results Homozygosity for a missense mutation, p.Cys846Gly, in one of the endosomal biogenesis core proteins, VPS11, was identified in all the patients. This was shown to be a founder mutation with a carrier frequency of 0.6% in the AJ population. The homologous yeast mutant had moderate impairment of fusion of the late endosome to the vacuole in Mup1-GFP transport assay.Conclusions We speculate that in neuronal cells, impairment of fusion of the late endosome to the vacuole would attenuate the degradation of plasma membrane receptors, thereby underlying the progressive neuronal phenotype in our patients. The VPS11 p.Cys846Gly mutation should be added to the AJ carrier screening panel.