Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis

Lucia Micale, Maria Giuseppina Turturo, Carmela Fusco, Bartolomeo Augello, Luis Perez-Jurado, Claudia Izzi, Maria Cristina Digilio, Donatella Milani, Elisabetta Lapi, Leopoldo Zelante, Giuseppe Merla

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Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta, which can occur sporadically as an autosomal dominant condition or as one component of the Williams-Beuren syndrome, a complex developmental genomic disorder associated with cardiovascular, neurobehavioral, craniofacial, and metabolic abnormalities, caused by a microdeletion at 7q11.23. We report the identification of seven novel mutations within the elastin gene in 31 familial and sporadic cases of nonsyndromic SVAS. Five are frameshift mutations within the coding region of the ELN gene that result in premature stop codons (PTCs); the other two mutations abolish the donor splice site of introns 3 and 28, respectively, and are predicted to alter splicing efficiency resulting in the generation of a PTC within the same introns of the gene. In vitro analysis using minigenes and cycloheximide showed that some selected frameshift mutant alleles are substrates of nonsense-mediated mRNA decay (NMD), confirming that the functional haploinsufficiency of the ELN gene is the main pathomechanism underlying SVAS. Interestingly, molecular analysis on patient fibroblasts showed that the c.20445GC mutant allele encodes for an aberrant shorter form of the elastin polypeptide that may hamper the normal assembly of elastin fibers in a dominant-negative manner.

Number of pages7
JournalEuropean Journal of Human Genetics
Issue number3
Publication statusPublished - 1 Mar 2010


  • 7q11.23
  • ELN
  • Haploinsufficiency
  • NMD
  • SVAS

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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