A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components of the intracellular membrane-tethering protein complexes, HOPS, and CORVET. Whole exome sequencing identified a novel VPS33A mutation in a patient suffering from a variant form of mucopolysaccharidosis. Electron and confocal microscopy, immunoblotting, and glycosphingolipid trafficking experiments were undertaken to investigate the effects of the mutant VPS33A in patient-derived skin fibroblasts. We describe an attenuated juvenile form of VPS33A-related syndrome—mucopolysaccharidosis plus in a man who is homozygous for a hitherto unknown missense mutation (NM_022916.4: c.599 G>C; NP_075067.2:p. Arg200Pro) in a conserved region of the VPS33A gene. Urinary glycosaminoglycan (GAG) analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid. We showed decreased abundance of VPS33A in patient derived fibroblasts and provided evidence that the p.Arg200Pro mutation leads to destablization of the protein and proteasomal degradation. As in the infantile form of mucopolysaccharidosis plus, the endocytic compartment in the fibroblasts also expanded—a phenomenon accompanied by increased endolysosomal acidification and impaired intracellular glycosphingolipid trafficking. Experimental treatment of the patient's cultured fibroblasts with the proteasome inhibitor, bortezomib, or exposure to an inhibitor of glucosylceramide synthesis, eliglustat, improved glycosphingolipid trafficking. To our knowledge this is the first report of an attenuated juvenile form of VPS33A insufficiency characterized by appreciable residual endosomal-lysosomal trafficking and a milder mucopolysaccharidosis plus than the disease in infants. Our findings expand the proof of concept of redeploying clinically approved drugs for therapeutic exploitation in patients with juvenile as well as infantile forms of mucopolysaccharidosis plus disease.

中文翻译：

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VPS33A 错义突变引起的幼年粘多糖贮积症

一种类似于婴儿粘多糖贮积症的罕见致命疾病，是由细胞内膜束缚蛋白复合物、HOPS 和 CORVET 的核心成分缺乏导致的细胞内吞运输受损引起的。全外显子组测序在一名患有变异型粘多糖贮积症的患者中发现了一个新的VPS33A突变。进行了电子和共聚焦显微镜、免疫印迹和糖脂运输实验，以研究突变体 VPS33A 在患者来源的皮肤成纤维细胞中的作用。我们描述了一种减弱的青少年形式的 VPS33A 相关综合征——黏多糖贮积症加上一个男性，该男性是保守区域中迄今未知的错义突变 (NM_022916.4: c.599 G>C; NP_075067.2:p. Arg200Pro) 的纯合子的VPS33A基因。尿糖胺聚糖 (GAG) 分析显示乙酰肝素、硫酸皮肤素和透明质酸增加。我们显示患者来源的成纤维细胞中 VPS33A 的丰度减少，并提供证据表明 p.Arg200Pro 突变导致蛋白质不稳定和蛋白酶体降解。与粘多糖贮积症的婴儿型一样，成纤维细胞中的内吞隔室也扩大了——这种现象伴随着内溶酶体酸化增加和细胞内糖鞘脂运输受损。用蛋白酶体抑制剂硼替佐米或暴露于葡萄糖神经酰胺合成抑制剂 eliglustat 对患者培养的成纤维细胞进行实验性治疗，改善了鞘糖脂的运输。据我们所知，这是第一份关于 VPS33A 功能不全的减毒幼年形式的报告，其特征是明显的残余内体-溶酶体运输和比婴儿疾病更温和的粘多糖贮积症。我们的研究结果扩展了重新部署临床批准的药物用于青少年和婴儿形式的粘多糖贮积症加上疾病患者的治疗开发的概念证明。