Cutis Laxa Arising from Frameshift Mutations in Exon 30 of the Elastin Gene (ELN)

Abstract

Congenital cutis laxa, a rare syndrome with marked skin laxity and pulmonary and cardiovascular compromise, is due to defective elastic fiber formation. In several cases, skin fibroblast tropoelastin production is markedly reduced yet reversed in vitro by transforming growth factor-␤ treatment. We previously showed that this reversal was due to elastin mRNA stabilization in one cell strain, and here this behavior was confirmed in skin fibroblasts from two generations of a second family. cDNA sequencing and heteroduplex analysis of elastin gene transcripts from three fibroblast strains in two kindreds now identify two frameshift mutations (2012⌬G and 2039⌬C) in elastin gene exon 30, thus leading to missense C termini. No other mutations were present in the ELN cDNA sequences of all three affected individuals. Transcripts from both alleles in each kindred were unstable and responsive to transforming growth factor-␤. Exons 22, 23, 26A, and 32 were always absent. Since exon 30 underwent alternative splicing in fibroblasts, we speculate that a differential splicing pattern could conceivably lead to phenotypic rescue. These two dominant-acting, apparently de novo mutations in the elastin gene appear to be responsible for qualitative and quantitative defects in elastin, resulting in the cutis laxa phenotype.

Modification and functional inactivation of the tropoelastin carboxy-terminal domain in cross-linked elastin

“…The data from the current study are consistent with this model and suggest that domain-36 may function to facilitate fiber maturation by forming an initial cross-link that serves to help register the multiple tropoelastin crosslinking sites for efficient oxidation by lysyl oxidase. A crosslinking function would explain why mutations that alter the domain-36 sequence, such as frame shift mutations associated with dominant cutis laxa (Szabo et al, 2006;Zhang et al, 1999), have detrimental effects on elastic fiber assembly.…”

“…This region of the protein is highly conserved (Chung et al, 2006) and interacts with microfibrillar proteins (Brown-Augsburger et al, 1994), integrins (Rodgers and Weiss, 2004) and sulfated proteoglycans (Broekelmann et al, 2005). An autosomal dominant form of cutis laxa has been linked to mutations that alter the sequence of this region of the molecule (Szabo et al, 2006;Zhang et al, 1999).…”

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

“…Some patients carry mutations in the elastin (ELN) or fibulin 5 (FBLN5) gene. 5,6 Autosomal recessive CL (ARCL) is the most prevalent and variable form of inherited neonatal CL. ARCL is divided in three major groups: type 1, 2 and 3 (ARCL1, MIM 219100; ARCL2A, MIM 219200; ARCL2B, MIM 612940; WSS, MIM 278250; ARCL3A, MIM 219150; ARCL 3B, MIM 614438; geroderma osteodysplasticum (GO), MIM 231070; De Barsy Syndrome (DBS), MIM 219150; macrocephaly, alopecia, CL, scoliosis syndrome (MACS), MIM 613075).…”

Elastin: mutational spectrum in supravalvular aortic stenosis

“…Abnormalities of elastic fibres, which are composed mainly of amorphous elastic (95%) and microfibrils, cause several cardiovascular, connective tissue and skin disorders, including Marfan syndrome, supravalvular aortic stenosis (SVAS) and Cutis Laxa. [1][2][3][4] SVAS is an obstructive vascular lesion with an incidence of 1/20 000 births, described in 1842 by Chevers,5 and was the first disorder to be associated with the elastin gene (ELN). The aortic narrowing can occur as a discrete hourglass deformity or as diffuse aortic hypoplasia and may be associated with other vascular lesions, the association with pulmonary arterial stenoses being well recognised.…”