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.
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Zsolt Urbán & Charles D. Boyd
Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA, USA
Virginia V. Michels & Stephen N. Thibodeau
Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA, USA
Elaine C. Davis
Institut Necker – IFREM Hôpital des Enfants-Malades, Paris 75743, France, France
Jean-Paul Bonnefont & Arnold Munnich
Center for Human Genetics, Leuven, B-3000, Belgium, Belgium
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Electronic Publication
About this article Cite this articleUrbán, Z., Michels, V., Thibodeau, S. et al. Isolated supravalvular aortic stenosis: functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay. Hum Genet 106, 577–588 (2000). https://doi.org/10.1007/s004390000285
Received: 03 January 2000
Accepted: 06 March 2000
Published: 18 May 2000
Issue Date: June 2000
DOI: https://doi.org/10.1007/s004390000285
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