1. ¹Institut de Biologie et de Chimie des Protéines, Centre National de la Recherche Scientifique, Université Lyon 1, Institut Fédératif de Recherches 128, Lyon, France
2. ²Centre National de Génotypage, Institut de Génomique, CEA, Evry, France
3. ³Dermatology Medical Center, Hotel-Dieu de France de Beirut, Beirut, Lebanon
4. ⁴Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon
5. ⁵Centre Commun d'Imagerie de Laennec, Faculté de Médecine R.T.H. Laennec, Université Lyon 1, Lyon, France
6. ⁶Généthon, Banque d'ADN et de cellules, Evry, France
7. ⁷Association Française contre les Myopathies, Evry, France
8. ⁸Laboratoire des Substituts Cutanés, Hôpital Edouard Herriot, Lyon, France

Correspondence: Pascal Sommer, Institut de Biologie et Chimie des Protéines, CNRS UMR 5086, 7 Passage du Vercors, Lyon cedex 07 69367, France. E-mail: p.sommer@ibcp.fr

Received 22 March 2007; Revised 24 October 2007; Accepted 27 October 2007; Published online 10 January 2008.

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.