Websites used: www.LOVD.nl/ATM
A-TWinnipeg: Pathogenesis of rare ATM missense mutation c.6200C>A with decreased protein expression and downstream signaling, early-onset dystonia, cancer, and life-threatening radiotoxicity
Article first published online: 13 MAR 2014
© 2014 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Molecular Genetics & Genomic Medicine
Volume 2, Issue 4, pages 332–340, July 2014
How to Cite
Nakamura, K., Fike, F., Haghayegh, S., Saunders-Pullman, R., Dawson, A. J., Dörk, T. and Gatti, R. A. (2014), A-TWinnipeg: Pathogenesis of rare ATM missense mutation c.6200C>A with decreased protein expression and downstream signaling, early-onset dystonia, cancer, and life-threatening radiotoxicity. Molecular Genetics & Genomic Medicine, 2: 332–340. doi: 10.1002/mgg3.72
- Issue published online: 10 JUL 2014
- Article first published online: 13 MAR 2014
- Manuscript Accepted: 2 FEB 2014
- Manuscript Revised: 29 JAN 2014
- Manuscript Received: 13 DEC 2013
- U.S.P.H.S. National Institutes of Health. Grant Numbers: 1R01NS052528, 5K02NS073836
- A-T Ease Foundation
- A-T Medical Research Foundation
- A-T Society
- NIH. Grant Number: NS073836
- cancer susceptibility;
- cDNA sequencing;
- missense mutation;
We studied 10 Mennonite patients who carry the c.6200C>A missense mutation (p.A2067D) in the ATM gene, all of whom exhibited a phenotypic variant of ataxia-telangiectasia (A-T) that is characterized by early-onset dystonia and late-onset mild ataxia, as previously described. This report provides the pathogenetic evidence for this mutation on cellular functions. Several patients have developed cancer and subsequently experienced life-threatening adverse reactions to radiation (radiotoxicity) and/or chemotherapy. As the c.6200C>A mutation is, thus far, unique to the Mennonite population and is always associated with the same haplotype or haplovariant, it was important to rule out any possible confounding DNA variant on the same haplotype. Lymphoblastoid cells derived from Mennonite patients expressed small amounts of ATM protein, which had no autophosphorylation activity at ATM Ser1981, and trace-to-absent transphosphorylation of downstream ATM targets. A-T lymphoblastoid cells stably transfected with ATM cDNA which had been mutated for c.6200C>A did not show a detectable amount of ATM protein. The same stable cell line with mutated ATM cDNA also showed a trace-to-absent transphosphorylation of downstream ATM targets SMC1pSer966 and KAP1pSer824. From these results, we conclude that c.6200A is the disease-causing ATM mutation on this haplotype. The presence of at least trace amounts of ATM kinase activity on some immunoblots may account for the late-onset, mild ataxia of these patients. The cause of the dystonia remains unclear. Because this dystonia-ataxia phenotype is often encountered in the Mennonite population in association with cancer and adverse reactions to chemotherapy, an early diagnosis is important.