title: Vacuolar H+-ATPase meets glycosylation in patients with cutis laxa.
abstract: Glycosylation of proteins is one of the most important post-translational modifications. Defects in the glycan biosynthesis result in congenital malformation syndromes, also known as congenital disorders of glycosylation (CDG). Based on the iso-electric focusing patterns of plasma transferrin and apolipoprotein C-III a combined defect in N- and O-glycosylation was identified in patients with autosomal recessive cutis laxa type II (ARCL II). Disease-causing mutations were identified in the ATP6V0A2 gene, encoding the a2 subunit of the vacuolar H(+)-ATPase (V-ATPase). The V-ATPases are multi-subunit, ATP-dependent proton pumps located in membranes of cells and organels. In this article, we describe the structure, function and regulation of the V-ATPase and the phenotypes currently known to result from V-ATPase mutations. A clinical overview of cutis laxa syndromes is presented with a focus on ARCL II. Finally, the relationship between ATP6V0A2 mutations, the glycosylation defect and the ARCLII phenotype is discussed.
authors.affiliation: Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Mailys
authors.initials: M
authors.lastname: Guillard
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Dimopoulou
authors.forename: Björn
authors.initials: B
authors.lastname: Fischer
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III / Q000235:genetics; D002462:Cell Membrane / Q000201:enzymology; D018981:Congenital Disorders of Glycosylation / Q000235:genetics; D003483:Cutis Laxa / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D005808:Genes, Recessive; D006031:Glycosylation; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010641:Phenotype; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000235:genetics*; D013347:Subcellular Fractions / Q000201:enzymology; D014168:Transferrin / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000502:physiology*
chemical_list: C525845:ATP6V0A2 protein, human; D053305:Apolipoprotein C-III; D021122:Protein Subunits; D014168:Transferrin; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases