title: Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes.
abstract: Cutis laxa (CL) is a condition characterized by redundant, pendulous, and inelastic skin. Acquired CL has been reported in patients with inflammatory diseases. The goal of this study was to investigate whether genetic lesions predispose patients to the development of acquired CL. We report a patient who developed CL following a Toxocara canis parasitism. He later had an aortic root aneurysm that required surgical correction. Histological evaluation showed inflammation followed by destruction of elastic fibers in both the skin and the aorta. Mutational analysis showed that the patient was heterozygous for an inherited fibulin-5 (FBLN5) allele G202R and compound heterozygous for elastin (ELN) alleles A55V and G773D. Western blotting indicated abnormal proteolytic processing of tropoelastin (TE) in patient fibroblasts. The FBLN5 202R allele on the other hand led to increased interaction of FBLN5 and TE and increased deposition of insoluble ELN partially rescuing the deficiency conferred by ELN mutation G773D. We demonstrated that the interaction of ELN and FBLN5 alleles results in elastic fibers susceptible to inflammatory destruction. These results suggest that the pathogenesis of acquired CL involves an underlying genetic susceptibility and highlight the importance of molecular genetic analysis in patients with idiopathic connective tissue disorders.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Qirui
authors.initials: Q
authors.lastname: Hu
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Reymond
authors.forename: Nicole
authors.initials: N
authors.lastname: Pinel
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Zabot
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Urban
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000473:pathology; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D003483:Cutis Laxa / Q000235:genetics* / Q000469:parasitology / Q000473:pathology; D003872:Dermatitis / Q000473:pathology*; D004547:Elastic Tissue / Q000473:pathology*; D004549:Elastin / Q000032:analysis / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000032:analysis / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011994:Recombinant Proteins / Q000032:analysis / Q000235:genetics*; D017166:Toxocara canis; D014120:Toxocariasis / Q000469:parasitology
chemical_list: D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; D011994:Recombinant Proteins; D004549:Elastin