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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
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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
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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
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Journal Article
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
2014
Overview
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. We describe and characterize a specific missense change in the ATM gene that associates with a very atypical A‐T phenotype of early‐onset dystonia, mild ataxia, as well as a high cancer risk and hypersensitivity to radiation therapy and chemotherapy. We identify a unique mutation in the ATM gene, c.6200C>A, and a unique associated STR (short tandem repeat) haplotype, and demonstrate with stable transfectants that, although the wild‐type ATM transcript (6200C variant) abrogates the cellular phenotype of A‐T cells, an otherwise identical transcript containing the 6200A variant does not. We show that this mutation is unique, to date, in Mennonite Anabaptists.
