title: 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.
abstract: 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.
authors: Department of Pathology and Laboratory Medicine, UCLA School of Medicine Los Angeles, California.
authors: Kotoka
authors: K
authors: Nakamura
authors: Department of Pathology and Laboratory Medicine, UCLA School of Medicine Los Angeles, California.
authors: Francesca
authors: F
authors: Fike
authors: Department of Pathology and Laboratory Medicine, UCLA School of Medicine Los Angeles, California.
authors: Sara
authors: S
authors: Haghayegh
authors: Department of Neurology, Albert Einstein College of Medicine Bronx, New York.
authors: Rachel
authors: R
authors: Saunders-Pullman
authors: Cytogenetics Laboratory, Division of Laboratory Medicine & Pathology, Departments of Biochemistry & Medical Genetics and Pediatrics & Child Health, Diagnostic Services of Manitoba, University of Manitoba Winnipeg, Manitoba, Canada.
authors: Angelika J
authors: AJ
authors: Dawson
authors: Gynaecology Research Unit, Hannover Medical School Hannover, Germany.
authors: Thilo
authors: T
authors: Dörk
authors: Department of Pathology and Laboratory Medicine, UCLA School of Medicine Los Angeles, California ; Department of Human Genetics, UCLA School of Medicine Los Angeles, California ; Molecular Biology Institute, UCLA Los Angeles, California.
authors: Richard A
authors: RA
authors: Gatti
keywords: ATM; Ataxia; cDNA sequencing; cancer susceptibility; dystonia; missense mutation; radiosensitivity; telangiectasia