Genomic instability in the type II TGF-β1 receptor gene in atherosclerotic and restenotic vascular cells
Journal of Clinical Investigation
Cardiovascular disease; DNA mutations; Microsatellite instability; Receptors; TGF-β
Cells proliferating from human atherosclerotic lesions are resistant to the antiproliferative effect of TGF-β1, a key factor in wound repair. DNA from human atherosclerotic and restenotic lesions was used to test the hypothesis that microsatellite instability leads to specific loss of the Type II receptor for TGF-β1 (TβR-H), causing acquired resistance to TGF-β1. High fidelity PCR and restriction analysis was adapted to analyze deletions in an A10 microsatellite within TβR-II. DNA from lesions, and cells grown from lesions, showed acquired 1 and 2 bp deletions in TβR-II, while microsatellites in the hMSH3 and hMSH6 genes, and hypermutable regions of p53 were unaffected. Sequencing confirmed that these deletions occurred principally in the replication error-prone A10 microsatellite region, though nonmicrosatellite mutations were observed. The mutations could be identified within specific patches of the lesion, while the surrounding tissue, or unaffected arteries, exhibited the wild-type genotype. This microsatellite deletion causes frameshift loss of receptor function, and thus, resistance to the antiproliferative and apoptotic effects of TGF-β1. We propose that microsatellite instability in TβR-II disables growth inhibitory pathways, allowing monoclonal selection of a disease-prone cell type within some vascular lesions.
McCaffrey, T., Du, B., Consigli, S., Szabo, P., Bray, P., Hartner, L., Weksler, B., Sanborn, T., Bergman, G., & Bush, H. (1997). Genomic instability in the type II TGF-β1 receptor gene in atherosclerotic and restenotic vascular cells. Journal of Clinical Investigation, 100 (9). http://dx.doi.org/10.1172/JCI119754