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

Man-Cong Zhang,Lan He,Mariagabriella Giro,Siu Li Yong,George E Tiller,Jeffrey M Davidson

doi:10.1074/jbc.274.2.981

Man-Cong Zhang, Lan He + Show 4 more

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https://doi.org/10.1074/jbc.274.2.981

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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-beta 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 (2012DeltaG and 2039DeltaC) 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-beta. 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.

Highlights

Congenital cutis laxa, a rare syndrome with marked skin laxity and pulmonary and cardiovascular compromise, is due to defective elastic fiber formation
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 identify two frameshift mutations (2012⌬G and 2039⌬C) in elastin gene exon 30, leading to missense C termini
A Frameshift Mutation of elastin gene (ELN) in Cutis Laxa Strain K.T.—A single base deletion (2012⌬G) in exon 30 of ELN was initially identified by direct sequencing of the RT-PCR products from patient fibroblasts (Fig. 1)

Summary

THE JOURNAL OF BIOLOGICAL CHEMISTRY

981–986, 1999 Printed in U.S.A. Cutis Laxa Arising from Frameshift Mutations in Exon 30 of the Elastin Gene (ELN)*. 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-␤. 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. Decreased or aberrant deposition of elastic fibers in certain tissues is characteristic of Marfan’s syndrome [13], supravalvular aortic stenosis (SVAS) (14 –16), and cutis laxa [6, 17]. We describe heterozygosity for a frameshift mutation (2012⌬G) in ELN in this cutis laxa patient and a similar mutation in two generations of a second cutis laxa family (2039⌬C), which we propose to be responsible for defects in tropoelastin production

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DISCUSSION