Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis.
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.
Laboratory of Medical Genetics, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Lucia
L
Micale
Maria Giuseppina
MG
Turturo
Carmela
C
Fusco
Bartolomeo
B
Augello
Luis A Pérez
LA
Jurado
Claudia
C
Izzi
Maria Cristina
MC
Digilio
Donatella
D
Milani
Elisabetta
E
Lapi
Leopoldo
L
Zelante
Giuseppe
G
Merla
D021921:Aortic Stenosis, Supravalvular / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D015331:Cohort Studies; D003513:Cycloheximide / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004549:Elastin / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D022821:RNA Splice Sites; D012333:RNA, Messenger; D004549:Elastin; D003513:Cycloheximide