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.

Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema

“…Similarly, individuals with elastin mutations linked to autosomal dominant cutis laxa have severe, very early onset emphysema (53). Like the G773D polymorphism, the cutis laxa mutations alter the functionality and perhaps stability of the elastic fiber (21). The result is a fiber that can support normal lung development but is more easily damaged and degraded when exposed to degradative enzymes or oxidative stress.…”

Elastic fibres in health and disease

“…Mutations in elastin and elastic fibre-associated proteins cause disease through loss or gain of function, and increased susceptibility to inflammatory or proteolytic damage of elastic fibres (Refs 122,123). Supravalvular aortic stenosis (SVAS; OMIM 185500) occurs in 1 in 20 000 live births, is inherited in an autosomal dominant manner but can also occur sporadically and is characterised by narrowing or obstruction of the ascending aorta.…”

Altered TGFβ signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency

“…Given these observations, we suggest that mutations in FBLN4 impair the stability and/or secretion of fibulin-4, similar to previous findings for fibulin-5 mutations. 34 The resulting decrease of protein in the extracellular matrix leads to altered interactions with fibulin-4 binding partners and, subsequently, to impaired elastogenesis. Fibulin-4 is known to associate with tropoelastin, possibly connecting elastin to microfibrils to form elastic fibers.…”