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

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Magda Cannata SerioDirk J Lefeber

Abstract

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. 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....Continue Reading

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Citations

Jun 20, 2020·Journal of Inherited Metabolic Disease·Jos C JansenDirk J Lefeber
Jul 8, 2020·International Journal of Molecular Sciences·Peter T A LindersGeert van den Bogaart
Oct 21, 2020·International Journal of Molecular Sciences·Agnes L Hipgrave EderveenManfred Wuhrer
Feb 19, 2021·Frontiers in Endocrinology·Aldo GrefhorstAdriaan G Holleboom
Apr 13, 2021·Frontiers in Physiology·Qianghua XiaYongjie Wei
Sep 30, 2020·Biochimica Et Biophysica Acta. General Subjects·Nina OndruskovaJaak Jaeken
Jul 17, 2021·The Journal of Biological Chemistry·Rebecca A OotStephan Wilkens
Aug 7, 2021·Biochimica Et Biophysica Acta. General Subjects·Matthew P Wilson, Gert Matthijs
Sep 12, 2021·Journal of Translational Medicine·Hong-Yu ShenWei-Fei Fan
Jun 27, 2021·Journal of Pediatric Gastroenterology and Nutrition·Rossella ColantuonoClaudia Mandato
Oct 10, 2021·Cellular and Molecular Gastroenterology and Hepatology·Lars E LarsenAdriaan G Holleboom

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Methods Mentioned

BETA
glycosylation
biopsy
exome sequencing
PCR
transfection

Software Mentioned

ImageJ
JACoP

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