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

• Published in: European journal of human genetics : EJHG Vol. 18; no. 3; pp. 317 - 323
• Main Authors: MICALE, Lucia, GIUSEPPINA TURTURO, Maria, MERLA, Giuseppe, FUSCO, Carmela, AUGELLO, Bartolomeo, PEREZ JURADO, Luis A, IZZI, Claudia, DIGILIO, Maria Cristina, MILANI, Donatella, LAPI, Elisabetta, ZELANTE, Leopoldo
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-03-2010
• Subjects: Alleles; Aorta; Aortic Stenosis, Supravalvular - genetics; Base Sequence; Biological and medical sciences; Cardiology. Vascular system; Cell Line; Coding; Codons; Cohort Studies; Cycloheximide; Cycloheximide - pharmacology; DNA Mutational Analysis; Elastin; Elastin - genetics; Endocardial and cardiac valvular diseases; Fibers; Fibroblasts; Frameshift mutant; Frameshift mutation; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation - drug effects; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Haploinsufficiency; Heart; Humans; Introns; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; mRNA turnover; Mutation; Mutation - genetics; Nonsense-mediated mRNA decay; Patients; Polypeptides; RNA Splice Sites - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Splicing; Stenosis; Italy; Spain; Human; NMD; Elastin; 7q11.23; ELN; Cardiovascular disease; Patient; Identification; Congenital disease; Supravalvular aortic stenosis; Arterial disease; Vascular disease; Characterization; SVAS; haploinsufficiency; Gene; Cardiac valvular disease; Cohort study; Genetics; Mutation; Aortic disease
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2009.181

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.2044+5G>C 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.