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Microsatellite mutation of type II transforming growth factor-beta receptor is rare in atherosclerotic plaques
K J Clark1, N R Cary, A A Grace
1Department of Oncology, MRC Centre, University of Cambridge, Cambridge, UK. kc216@mole.bio.cam.ac.uk
Abstract:
A somatic mutation within a microsatellite polyA tract in the coding region of the type II transforming growth factor (TGF)-beta receptor gene was reported to occur in human atherosclerotic and restenotic lesions. This mutation occurs frequently in colorectal cancer with the replication error repair phenotype and results in loss of sensitivity to the growth inhibitory effects of TGF-beta in cells from the tumors. The mutation was proposed to account for the clonal expansion of vascular smooth muscle cells observed in atherosclerotic plaques, through loss of the growth inhibitory effect of TGF-beta. The frequency of the mutation and the extent of clonal expansion of the mutated cells have major implications for the mechanism of atherogenesis and therapeutic strategies. We analyzed a set of 22 coronary arterial and 9 aortic samples containing early to advanced atherosclerotic lesions for the mutation in the type II TGF-beta receptor polyA tract. Only 1 coronary arterial sample from an advanced lesion showed detectable amounts of the mutation, present at a low level (8% of the DNA sample). The data imply that the mutation occurs only at low frequency and is not a major mechanistic contributor to the development of atherosclerosis.
Insights
A specific gene mutation in transforming growth factor (TGF)-beta receptor was investigated for its role in atherosclerosis. This mutation was found at very low levels in human arterial samples, suggesting it is not a major cause of atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Cancer Biology
Background:
- Somatic mutations in the type II transforming growth factor (TGF)-beta receptor gene's polyA tract are linked to colorectal cancer.
- This mutation causes loss of TGF-beta growth inhibition, proposed as a mechanism for vascular smooth muscle cell clonal expansion in atherosclerosis.
Purpose of the Study:
- To investigate the frequency and significance of the type II TGF-beta receptor polyA tract mutation in human atherosclerotic lesions.
- To determine if this mutation contributes mechanistically to atherogenesis.
Main Methods:
- Analysis of DNA from 22 coronary arterial and 9 aortic samples with varying stages of atherosclerotic lesions.
- Detection of the specific polyA tract mutation in the type II TGF-beta receptor gene.
Main Results:
- The mutation was detected in only one coronary arterial sample (advanced lesion).
- The mutation was present at a low level (8% of the DNA sample) in the positive case.
- These findings indicate a low frequency of the mutation in atherosclerotic lesions.
Conclusions:
- The type II TGF-beta receptor polyA tract mutation occurs at a low frequency in human atherosclerotic lesions.
- The mutation is unlikely to be a major mechanistic contributor to the development of atherosclerosis.
- Further research may explore other factors in atherogenesis.