TY - JOUR
T1 - Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis
AU - Micale, Lucia
AU - Turturo, Maria Giuseppina
AU - Fusco, Carmela
AU - Augello, Bartolomeo
AU - Jurado, Luis A.Pérez
AU - Izzi, Claudia
AU - Digilio, Maria Cristina
AU - Milani, Donatella
AU - Lapi, Elisabetta
AU - Zelante, Leopoldo
AU - Merla, Giuseppe
N1 - Funding Information:
We are very grateful to the SVAS families, whose cooperation made this study possible. We thank Youngho Kim for ELN primer sequences. This study was conducted with the support of the Italian Ministry of Health (Ricerca Corrente 2006-2009), the Fondazione Banca del Monte di Foggia ‘Domenico Siniscalco Ceci’ and the Jérôme Lejeune Foundation to GM, and the VI Framework Program of the European Commission (LSHG-CT-2006-037627) to LAPJ.
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
KW - 7q11.23
KW - ELN
KW - Haploinsufficiency
KW - NMD
KW - SVAS
UR - http://www.scopus.com/inward/record.url?scp=77149168766&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2009.181
DO - 10.1038/ejhg.2009.181
M3 - Article
C2 - 19844261
AN - SCOPUS:77149168766
SN - 1018-4813
VL - 18
SP - 317
EP - 323
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 3
ER -