title: Further characterization of ATP6V0A2-related autosomal recessive cutis laxa.
abstract: Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debré type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H(+)-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-β signalling and increased TGF-β1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.
authors: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
authors: Björn
authors: B
authors: Fischer
authors: Aikaterini
authors: A
authors: Dimopoulou
authors: Johannes
authors: J
authors: Egerer
authors: Thatjana
authors: T
authors: Gardeitchik
authors: Alexa
authors: A
authors: Kidd
authors: Dominik
authors: D
authors: Jost
authors: Hülya
authors: H
authors: Kayserili
authors: Yasemin
authors: Y
authors: Alanay
authors: Iliana
authors: I
authors: Tantcheva-Poor
authors: Elisabeth
authors: E
authors: Mangold
authors: Cornelia
authors: C
authors: Daumer-Haas
authors: Shubha
authors: S
authors: Phadke
authors: Reto I
authors: RI
authors: Peirano
authors: Julia
authors: J
authors: Heusel
authors: Charu
authors: C
authors: Desphande
authors: Neerja
authors: N
authors: Gupta
authors: Arti
authors: A
authors: Nanda
authors: Emma
authors: E
authors: Felix
authors: Elisabeth
authors: E
authors: Berry-Kravis
authors: Madhulika
authors: M
authors: Kabra
authors: Ron A
authors: RA
authors: Wevers
authors: Lionel
authors: L
authors: van Maldergem
authors: Stefan
authors: S
authors: Mundlos
authors: Eva
authors: E
authors: Morava
authors: Uwe
authors: U
authors: Kornak
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D002478:Cells, Cultured; D002675:Child, Preschool; D003483:Cutis Laxa / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006031:Glycosylation / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D006180:Proton-Translocating ATPases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D055815:Young Adult
chemical_list: C525845:ATP6V0A2 protein, human; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D020126:Brefeldin A; D006180:Proton-Translocating ATPases