title: A p.C217R mutation in fibulin-5 from cutis laxa patients is associated with incomplete extracellular matrix formation in a skin equivalent model.
abstract: Cutis laxa (CL) is a rare genodermatosis, which is clinically and genetically heterogeneous. It is characterized by redundant, loose, sagging, and inelastic skin. In a consanguineous family from Lebanon with autosomal-recessive transmission, we identified a homozygous missense mutation (c.649T --> C; p.C217R) in the fibulin-5 gene (FBLN5), which was, to our knowledge, previously unreported. Small skin biopsies were performed, which permitted isolation of skin fibroblasts harboring this FBLN5 mutation; they exhibited a deficit in cell growth. A CL skin equivalent (CL-SE) model compared with control SE was successfully developed to define the behavior of CL fibroblasts in a three-dimensional model. There was increased cell death and a global extracellular matrix deficiency in the dermis of this CL-SE model, and a low level of the main elastic fiber expression. There was no basement membrane evident at the ultrastructural level, and type-VII collagen could not be detected at the histological level. This model reproduced some defects of the extracellular matrix and highlighted other defects, which occurred at the time of the basement membrane formation, which were not evident in skin from patients. This CL-SE model could be adapted to screen for therapeutically active molecules.
authors.affiliation: Institut de Biologie et de Chimie des Protéines, Centre National de la Recherche Scientifique, Université Lyon 1, Institut Fédératif de Recherches 128, Lyon, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Claus
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
authors.forename: Hala
authors.initials: H
authors.lastname: Mégarbané
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Florence
authors.initials: F
authors.lastname: Jobard
authors.forename: Romain
authors.initials: R
authors.lastname: Debret
authors.forename: Simone
authors.initials: S
authors.lastname: Peyrol
authors.forename: Safa
authors.initials: S
authors.lastname: Saker
authors.forename: Martine
authors.initials: M
authors.lastname: Devillers
authors.forename: Pascal
authors.initials: P
authors.lastname: Sommer
authors.forename: Odile
authors.initials: O
authors.lastname: Damour
mesh_terms: D001485:Basement Membrane / Q000378:metabolism; D024143:Collagen Type VII / Q000378:metabolism; D003483:Cutis Laxa / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D008954:Models, Biological; D009154:Mutation; D020125:Mutation, Missense; D012867:Skin / Q000473:pathology*
chemical_list: D024143:Collagen Type VII; D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human