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

• Published in: The Journal of biological chemistry 1999-01, Vol.274 (2), p.981-986
• Main Authors: Zhang, Man-Cong, He, Lan, Giro, MariaGabriella, Yong, Siu Li, Tiller, George E., Davidson, Jeffrey M.
• Format: Article
• Language: English
• Subjects: Alleles; Base Sequence; Cutis Laxa - congenital; Cutis Laxa - genetics; DNA Primers; Elastin - genetics; Exons; Frameshift Mutation; Humans; Infant, Newborn; Male; Molecular Sequence Data; RNA Splicing; RNA, Messenger - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.2.981

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-β 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 (2012ΔG and 2039ΔC) in elastin gene exon 30, thus leading to missense C termini. No other mutations were present in theELN cDNA sequences of all three affected individuals. Transcripts from both alleles in each kindred were unstable and responsive to transforming growth factor-β. 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.