1. Mutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease
- Author
-
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, Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Faculteit Medische Wetenschappen/UMCG, Medicum, Department of Pathology, University of Helsinki, and HUS Helsinki and Uusimaa Hospital District more...
- Subjects
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 - Abstract
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. more...
- Published
- 2020