Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A.
Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A.
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DOI：
10.1002/humu.24479
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发表时间：
2022-12
期刊：
影响因子：
3.9
通讯作者：
Cox, Timothy M.
中科院分区：
文献类型：
--
作者：
Pavlova, Elena, V;Lev, Dorit;Michelson, Marina;Yosovich, Keren;Michaeli, Hila Gur;Bright, Nicholas A.;Manna, Paul T.;Dickson, Veronica Kane;Tylee, Karen L.;Church, Heather J.;Luzio, J. Paul;Cox, Timothy M.
关键词：
一种类似婴儿粘多糖样沉积症的罕见致死性疾病，由细胞内膜栓系蛋白复合物核心组分HOPS和CORVET缺乏导致的细胞内吞运输受损引起。全外显子组测序鉴定了一种新的VPS 33 A突变的患者患有变异形式的粘多糖沉积症。进行电子和共聚焦显微镜、免疫印迹和鞘糖脂运输实验以研究突变VPS 33 A在患者来源的皮肤成纤维细胞中的作用。我们描述了一名VPS 33 A相关综合征的减毒幼年型-粘多糖样沉积症+，该患者在VPS 33 A基因保守区存在迄今未知的错义突变（NM_022916. 4：c. 599 G>C; NP_075067. 2：p. Arg 200 Pro），为纯合子。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VPS 33 A的丰度降低，并提供了p.Arg200Pro突变导致蛋白质不稳定和蛋白酶体降解的证据。在婴儿型的粘多糖沉积症加上，内吞隔室在成纤维细胞也扩大的现象伴随着增加内溶酶体酸化和受损的细胞内鞘糖脂运输。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，可改善鞘糖脂转运。据我们所知，这是第一份关于VPS 33 A功能不全减毒幼年型的报告，其特征是明显的残留内体-溶酶体运输和比婴儿疾病更轻的粘多糖样变性。我们的研究结果扩大了重新部署临床批准的药物用于治疗青少年和婴儿型粘多糖病加疾病患者的概念验证。
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.
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DOI：
10.1073/pnas.1307074110
发表时间：
2013-08-13
影响因子：
11.1
作者：
Graham, Stephen C.;Wartosch, Lena;Owen, David J.
通讯作者：
Owen, David J.
影响因子：
32.4
作者：
Garg S;Sharma M;Ung C;Tuli A;Barral DC;Hava DL;Veerapen N;Besra GS;Hacohen N;Brenner MB
通讯作者：
Brenner MB
影响因子：
4
作者：
Edvardson, Shimon;Gerhard, Frank;Elpeleg, Orly
通讯作者：
Elpeleg, Orly
影响因子：
4
作者：
Balderhaar, Henning J. Kleine;Ungermann, Christian
通讯作者：
Ungermann, Christian
影响因子：
15.9
作者：
ABO, T;RODER, JC;BALCH, CM
通讯作者：
BALCH, CM