Mutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease

Autor: Elzbieta Czarnowska, Magda Cannata Serio, Pavel Pichurin, Sharita Timal, Jos C. Jansen, Hannu Kalimo, Adriaan G. Holleboom, Can Ficicioglu, Margret Ryan, Johan W. Jonker, Richard J. Rodenburg, Linda Hasadsri, Angel Ashikov, Christian Gilissen, Miao He, W. Alfredo Ríos-Ocampo, Matias Simons, Lars E. Larsen, Dirk Lefeber, Berge A. Minassian, Alessandra Rugierri, Joris A. Veltman, Tom H. Stevens, Gwenn Le Meur, Eva Morava, Piotr Socha, Kimiyo Raymond, Laurie A. Graham
Přispěvatelé: Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Faculteit Medische Wetenschappen/UMCG, Medicum, Department of Pathology, University of Helsinki, HUS Helsinki and Uusimaa Hospital District
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Biopsy
DNA Mutational Analysis
chemistry.chemical_compound
Steatohepatitis/Metabolic Liver Disease
Congenital Disorders of Glycosylation
0302 clinical medicine
Lipid droplet
Nonalcoholic fatty liver disease
Cells
Cultured

Chemistry
Liver Diseases
CHOLESTEROL
Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]
Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
Pedigree
3. Good health
Cell biology
DEFICIENCY
Liver
030211 gastroenterology & hepatology
Original Article
Erratum
ENZYMES
Adult
Vacuolar Proton-Translocating ATPases
X-LINKED MYOPATHY
Primary Cell Culture
Mutation
Missense

ENDOPLASMIC-RETICULUM
Abnormal protein glycosylation
03 medical and health sciences
All institutes and research themes of the Radboud University Medical Center
Autophagy
medicine
Humans
VACUOLAR MEMBRANE
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
Hepatology
Cholesterol
Endoplasmic reticulum
Original Articles
Fibroblasts
medicine.disease
TRANSPORT
030104 developmental biology
3121 General medicine
internal medicine and other clinical medicine

Unfolded protein response
Steatosis
Congenital disorder of glycosylation
GOLGI HOMEOSTASIS
Zdroj: Hepatology (Baltimore, Md.)
Hepatology (Baltimore, Md.), 72(6), 1968-1986. John Wiley and Sons Ltd
Hepatology, 72, 6, pp. 1968-1986
Hepatology, 72(6), 1968-1986. Wiley
Hepatology, 72, 1968-1986
Hepatology
ISSN: 0270-9139
Popis: 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.
Databáze: OpenAIRE