We have screened the elastin gene for mutations responsible for supravalvular aortic stenosis (SVAS) in two large, independently collected families with isolated (nonsyndromic) SVAS. By single-strand conformation polymorphism and heteroduplex analysis, we have identified a C to G transversion within the acceptor splice site of exon 16 in SVAS patients from both families. This mutation segregates in both families with high penetrance of SVAS, and all affected individuals carry the mutation. Haplotype analysis by using closely linked polymorphisms, including a previously unreported BfaI restriction fragment length polymorphism within the 3’-UTR of the elastin gene, indicates that the mutations found in the two apparently non-overlapping kindreds are identical by descent. To study the effect of the mutation on the expression of the mutant allele, we have established a primary skin fibroblast culture from one of the affected individuals. Reverse transcription/polymerase chain reaction analysis of elastin mRNA species indicates that the mutation results in two abnormal elastin mRNA species. One mutant elastin mRNA is generated by the activation of a cryptic splice site that lies within intron 15 and that adds 44 bp of intronic sequence to the sequence encoded by exon 16. This insertion creates a frame shift that results in a 59-amino-acid-long abnormal protein sequence and leads to a termination codon in the mRNA sequence encoded by exon 17. The smaller abnormal mRNA species arises as a consequence of the skipping of exon 16. This study demonstrates, for the first time, the expression of mutant alleles of the elastin gene in patients with isolated SVAS.
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Similar content being viewed by others Explore related subjectsDiscover the latest articles and news from researchers in related subjects, suggested using machine learning. Author information Authors and AffiliationsPacific Biomedical Research Center, University of Hawaii, 1993 East-West Road, Honolulu, HI 96822, USA e-mail: cbkc08901@aol.com, Tel.: +1 808 956 6341, Fax: +1 808 956 9481, , , , , , US
Zsolt Urbán, Katalin Csiszár & C. D. Boyd
Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA, , , , , , US
Virginia V. Michels & Stephen N. Thibodeau
Department of Surgery, Division of Human Molecular Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA, , , , , , US
Helen Donis-Keller
Received: 24 April 1998 / Accepted: 30 September 1998
About this article Cite this articleUrbán, Z., Michels, V., Thibodeau, S. et al. Supravalvular aortic stenosis: a splice site mutation within the elastin gene results in reduced expression of two aberrantly spliced transcripts. Hum Genet 104, 135–142 (1999). https://doi.org/10.1007/s004390050926
Issue Date: March 1999
DOI: https://doi.org/10.1007/s004390050926
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