Mutations in ATP6AP2 cause autophagic liver disease in humans. Issue 6 (3rd June 2018)

• Record Type: Journal Article
• Authors: Cannata Serio, Magda; Rujano, Maria A.; Simons, Matias
• Is Part Of: Autophagy. Volume 14:Issue 6(2018)
• Page Start: 1088
• Page End: 1089
• Publication Date: 2018-06-03
• Subjects: acidification -- autophagy -- Drosophila -- endoplasmic reticulum -- human genetics -- lysosomes -- MTORC1 -- (pro)renin receptor -- V-ATPase; Autophagic vacuoles -- Periodicals; Apoptosis -- Periodicals; Cell death -- Periodicals; Lysosomes -- Periodicals; Degeneration (Pathology) -- Periodicals; Autophagy -- Periodicals; Cell Death -- Periodicals; Lysosomes -- Periodicals; Periodicals; 571.936
• DOI: 10.1080/15548627.2018.1434370
• Languages: English
• ISSNs: 1554-8627

Abstract

ABSTRACT: The biogenesis of the proton pump V-ATPase commences with the assembly of the proton pore sector V0 in the endoplasmic reticulum (ER). This process occurs under the control of a group of assembly factors whose mutations have recently been shown to cause glycosylation disorders with overlapping phenotypes in humans. Using whole exome sequencing, we demonstrate that mutations of the accessory V-ATPase subunit ATP6AP2 cause a similar disease characterized by hepatosteatosis, lipid abnormalities, immunodeficiency and cognitive impairment. ATP6AP2 interacts with members of the V0 assembly complex, and its ER localization is crucial for V-ATPase activity. Moreover, ATP6AP2 mutations can cause developmental defects and steatotic phenotypes when introduced into Drosophila. Altogether, our data suggest that these phenotypes are the result of a pathogenetic cascade that includes impaired V-ATPase assembly, defective lysosomal acidification, reduced MTOR signaling and autophagic misregulation.