Mutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease
Mutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease
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DOI：
10.1002/hep.31218
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发表时间：
2020-12-01
期刊：
影响因子：
13.5
通讯作者：
Lefeber, Dirk J.
中科院分区：
文献类型：
--
作者：
Cannata Serio, Magda;Graham, Laurie A.;Lefeber, Dirk J.
背景与目的细胞内H+-ATP复合物（V-ATP酶）是细胞内酸化所必需的多亚基蛋白复合物。已知至少有五种不同的因子对于其在内质网（ER）中的组装是必不可少的。这些V-ATP酶组装因子中的四个的遗传缺陷显示重叠的临床特征，包括脂肪性肝病和轻度高胆固醇血症。一个例外是组装因子空泡ATP酶组装膜蛋白（VMA 21），其X连锁突变导致自噬性myopathy.Approach和结果在这里，我们报告VMA 21在男性患者中的致病性变异异常蛋白糖基化，导致轻度胆汁淤积，慢性转氨酶升高，（低密度脂蛋白）胆固醇升高和肝细胞脂肪变性。我们还表明，VMA 21变体导致V-ATP酶错误组装和功能障碍。因此，溶酶体酸化和吞噬物质的降解受损，导致脂滴（LD）在自体溶酶体中蓄积。此外，VMA 21缺陷触发内质网应激和隔离未酯化的胆固醇在溶酶体中，从而激活甾醇反应元件结合蛋白介导的胆固醇synthesis pathways.Conclusions在一起，我们的数据表明，受损的脂肪吞噬，内质网应激，胆固醇合成增加导致LD积累和肝脂肪变性。因此，V-ATP酶组装缺陷是遗传性肝病的一种形式，与非酒精性脂肪性肝病的发病机制有关。
Background and Aims Vacuolar H+-ATP complex (V-ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V-ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X-linked mutations lead to autophagic myopathy.Approach and Results Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low-density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V-ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element-binding protein-mediated cholesterol synthesis pathways.Conclusions Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease.