Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN)

Congenital cutis laxa, a rare syndrome with marked skin laxity and pulmonar y and cardiovascular compromise, is due to defective elastic fiber formatio n. In several cases, skin fibroblast tropoelastin production is markedly re duced yet reversed in vitro by transforming growth factor-beta treatment. W e previously showed that this reversal was due to elastin mRNA stabilizatio n in one cell strain, and here this behavior was confirmed in skin fibrobla sts from two generations of a second family. cDNA sequencing and heterodupl ex analysis of elastin gene transcripts from three fibroblast strains in tw o kindreds now identify two frameshift mutations (2012 Delta G and 2039 Del ta 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 ind ividuals. Transcripts from both alleles in each kindred were unstable and r esponsive to transforming growth factor-beta. Exons 22, 23, 26A, and 32 wer e always absent. Since exon 30 underwent alternative splicing in fibroblast s, we speculate that a differential splicing pattern could conceivably lead to phenotypic rescue. These two dominant-acting, apparently de novo mutati ons in the elastin gene appear to be responsible for qualitative and quanti tative defects in elastin, resulting in the cutis laxa phenotype.