Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: Mutations with increased cancer risk

Mitui, M., Nahas, S. A., Du, L. T., Yang, Z., Lai, C. H., Nakamura, K., Arroyo, S., Scott, S., Purayidom, A., Concannon, P., Lavin, M. and Gatti, R. A. (2009) Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: Mutations with increased cancer risk. Human Mutation, 30 1: 12-21. doi:10.1002/humu.20805


Author Mitui, M.
Nahas, S. A.
Du, L. T.
Yang, Z.
Lai, C. H.
Nakamura, K.
Arroyo, S.
Scott, S.
Purayidom, A.
Concannon, P.
Lavin, M.
Gatti, R. A.
Title Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: Mutations with increased cancer risk
Journal name Human Mutation   Check publisher's open access policy
ISSN 1059-7794
1098-1004
Publication date 2009-01
Year available 2008
Sub-type Article (original research)
DOI 10.1002/humu.20805
Volume 30
Issue 1
Start page 12
End page 21
Total pages 10
Editor Haig H. Kazazian Jr.
Richard Cotton
Place of publication Hoboken, NJ, U.S.A.
Publisher John Wiley & Sons
Language eng
Subject 0604 Genetics
1103 Clinical Sciences
Formatted abstract
The functional consequences of missense variants are often difficult to predict. This becomes especially relevant when DNA sequence changes are used to determine a diagnosis or prognosis. To analyze the consequences of 12 missense variants in patients with mild forms of ataxia-telangiectasia (A-T), we employed site-directed mutagenesis of ataxia-telangiectasia mutated (ATM) cDNA followed by stable transfections into a single A-T cell line to isolate the effects of each allele on the cellular phenotype. After induction of the transfected cells with CdCl2, we monitored for successful ATM transcription and subsequently assessed: 1) intracellular ATM protein levels; 2) ionizing radiation (IR)-induced ATM kinase activity; and 3) cellular radiosensitivity. We then calculated SIFT and PolyPhen scores for the missense changes. Nine variants produced little or no correction of the A-T cellular phenotype and were interpreted to be ATM mutations; SIFT/PolyPhen scores supported this. Three variants corrected the cellular phenotype, suggesting that they represented benign variants or polymorphisms. SIFT and PolyPhen scores supported the functional analyses for one of these variants (c.1709T>C); the other two were predicted to be “not tolerated” (c.6188G>A and c.6325T>G) and were classified as “operationally neutral.” Genotype/phenotype relationships were compared: three deleterious missense variants were associated with an increased risk of cancer (c.6679C>T, c.7271T>G, and c.8494C>T). In situ mutagenesis represents an effective experimental approach for distinguishing deleterious missense mutations from benign or operationally neutral missense variants.
Keyword Missense mutations
Mutagenesis
ATM
Cancer risk
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Article first published online: 16 JUL 2008.

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
School of Medicine Publications
 
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Created: Thu, 03 Sep 2009, 08:51:19 EST by Mr Andrew Martlew on behalf of Queensland Institute of Medical Research