ArticleHepatology (Baltimore, Md.)2020
Mutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease.
Article in Hepatology (Baltimore, Md.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 52 citations in OpenAlex.
- Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking.Biomolecules · 2026Article
- Genome-wide detection of human 5' UTR variants that impact protein translation.American journal of human genetics · 2026Article
- ATP6V1B2 alleviates hepatic steatosis by promoting lysosomal acidification in hepatocytes.Cell death discovery · 2026Article
- Untargeted Metabolomics for Diagnosis, Monitoring, and Understanding the Pathophysiology of Inherited Metabolic Disorders.Journal of inherited metabolic disease · 2026Review
- Failure of lysosomal acidification and endomembrane network in neurodegeneration.Experimental & molecular medicine · 2025Review
- Control of Golgi- V-ATPase through Sac1-dependent co-regulation of PI(4)P and cholesterol.Nature communications · 2025Article
- Genome-wide identification of modulators of Chlamydia trachomatis parasitophorous vacuole stability highlights an important role for sphingolipid supply.PLoS biology · 2025Article
- Recent advances in the clinical spectrum and pathomechanisms associated with X-linked myopathy with excessive autophagy and otherJournal of neuromuscular diseases · 2025Review
- An update on autophagy disorders.Journal of inherited metabolic disease · 2025Review
- Dmxl1 Is an Essential Mammalian Gene that Is Required for V-ATPase Assembly and Function In Vivo.Function (Oxford, England) · 2024Article
- Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis.Human molecular genetics · 2023Article
- Review
- Elevated oxysterol and N-palmitoyl-O-phosphocholineserine levels in congenital disorders of glycosylation.Journal of inherited metabolic disease · 2023Article
- Structural basis of V-ATPase VProceedings of the National Academy of Sciences of the United States of America · 2023Article
- The cytosolic N-terminal domain of V-ATPase a-subunits is a regulatory hub targeted by multiple signals.Frontiers in molecular biosciences · 2023Review
- Follicular lymphoma-associated mutations in the V-ATPase chaperone VMA21 activate autophagy creating a targetable dependency.Autophagy · 2022Article
- Expanding the phenotype ofCold Spring Harbor molecular case studies · 2022Article
- CDG or not CDG.Journal of inherited metabolic disease · 2022Article
- Erratum for Cannata Serio et al. Mutations in the V-ATPase assembly factor VMA21 cause a congenital disorder of glycosylation with autophagic liver disease.Hepatology (Baltimore, Md.) · 2022Article
- Fluorescence Lifetime Imaging of pH along the Secretory Pathway.ACS chemical biology · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
28 authors at 13 institutions in 8 countries.
Funding
Abstract
BACKGROUND AND
aimsVacuolar 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
resultsHere, 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.
conclusionsTogether, 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.
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