Aberrant splicing of the ATM gene associated with shortening of the intronic mononucleotide tract in human colon tumor cell lines: A novel mutation target of microsatellite instability
✍ Scribed by Yosuke Ejima; Lichun Yang; Masao S. Sasaki
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- French
- Weight
- 181 KB
- Volume
- 86
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Inherited mutations of the ATM gene are responsible for the human autosomal recessive disorder ataxia-telangiectasia (A-T) characterized by pleiotropic clinical manifestations. ATM mutations are also involved in the development of sporadic human cancers such as T-cell prolymphocytic leukemia and B-cell chronic lymphocytic leukemia. Little is known, however, on the association of ATM mutations with nonlymphoid malignancy. Here, we analyzed a panel of cell lines derived from human solid tumors for the presence of ATM mutations. PCR-SSCP analysis of 25 tumor cell lines revealed 50 sequence alterations in 16 cell lines. The most striking feature was a high frequency of deletions within the intronic mononucleotide tracts exclusively in the 5 colon tumor cell lines with microsatellite instability, which accounted for 62% of the sequence alterations observed here. Generation of aberrant splicing variants (497del22 or 1236del372) was associated with 2 such intronic deletions at splice acceptor sites preceding ATM exon 8 or exon 12, respectively. The level of ATM protein was partially depressed in the 3 cell lines where expression of protein-truncating 497del22 transcripts dominated. This implies that ATM is a novel mutation target of microsatellite instability where abnormal transcripts are generated indirectly by intronic mutations, which is distinct from the other mutation targets such as the type II TGF- receptor gene or BAX, where exonic repeats are directly affected. Int.