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Free keywords:
Adolescent
Adult
Apoptosis
Blotting, Western
Brefeldin A/pharmacology
Cells, Cultured
Child, Preschool
Cutis Laxa/ congenital/genetics/metabolism/pathology
Enzyme-Linked Immunosorbent Assay
Fibroblasts/drug effects/metabolism/pathology
Fluorescent Antibody Technique
Glycosylation/drug effects
Golgi Apparatus/drug effects/metabolism
Humans
Infant
Male
Mutation/ genetics
Protein Synthesis Inhibitors/pharmacology
Protein Transport/drug effects
Proton-Translocating ATPases/ genetics
RNA, Messenger/genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Skin/drug effects/metabolism/pathology
Transforming Growth Factor beta1/ metabolism
Young Adult
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), Debre 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-beta signalling and increased TGF-beta1 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.
