Isolated supravalvular aortic stenosis: Functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay

Zsolt Urbán, Virginia V. Michels, Stephen N. Thibodeau, Elaine C. Davis, Jean Paul Bonnefont, Arnold Munnich, Benedicte Eyskens, Marc Gewillig, Koen Devriendt, Charles D. Boyd

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

We have used single-strand conformation and heteroduplex analyses of genomic amplimers to identify point mutations within the elastin gene (ELN) in patients with non-syndromic supravalvular aortic stenosis (SVAS) from a total of eight unrelated families. Six novel point mutations were identified. We have collected detailed clinical information on mutation carriers and demonstrated significant non-penetrance in some of the families. Together with the new mutations described here, 14 point mutations have been reported in SVAS patients, and 10 of these result in premature stop codons (PTCs). We have analyzed the expression of ELN alleles in skin fibroblasts from one SVAS patient and shown that PTC mutations indeed result in selective elimination of mutant transcripts. Inhibition of the nonsense-mediated decay mechanism by cycloheximide resulted in the stabilization of mutant elastin mRNA. Allelic inactivation by the ELN mutation in this patient led to an overall decrease of the steady state levels of elastin mRNA. Finally, we have demonstrated reduced synthesis and secretion of tropoelastin by skin fibroblasts from the same SVAS patient. We conclude that PTC mutations in ELN result in nonsense-mediated decay of mutant mRNA in this patient. Given the predominance of PTC mutations in SVAS, we suggest that functional haploinsufficiency may be a pathomechanism underlying most cases of non-syndromic SVAS.

Original languageEnglish (US)
Pages (from-to)577-588
Number of pages12
JournalHuman genetics
Volume106
Issue number6
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Isolated supravalvular aortic stenosis: Functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay'. Together they form a unique fingerprint.

  • Cite this

    Urbán, Z., Michels, V. V., Thibodeau, S. N., Davis, E. C., Bonnefont, J. P., Munnich, A., Eyskens, B., Gewillig, M., Devriendt, K., & Boyd, C. D. (2000). Isolated supravalvular aortic stenosis: Functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay. Human genetics, 106(6), 577-588. https://doi.org/10.1007/s004390050028