A‐T_Winnipeg: 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.

Ataxia‐telangiectasia: recommendations for multidisciplinary treatment

“…3 Female patients have been reported to give birth to typically developing children. 3,[144][145][146]…”

Ataxia-telangiectasia

“…In these cases, regulatory, missense, or leaky splicing ATM mutations and a residual ATM activity were detected. 4 The genotype of our patient is characterized by an inframe deletion and a missense mutation without residual ATM activity. Accordingly, a classic presentation and outcome should have been expected.…”

“…Milder variants (late-onset, slowly progressive ataxia/dyskinesia syndrome) have been associated not only with missense ATM mutations and residual ATM kinase activity 3 but also with the classic severe genotype and absent ATM protein. 4 …”

ATM (ataxia telangiectasia mutated)

“…The corresponding ATM genotypes are combinations of hypomorphic alleles or combinations of null and hypomorphic ones. Many of the latter are leaky splicing mutations and others are missense mutations, eventually yielding low amounts of active ATM Alterman N et al, 2007;Soresina A et al, 2008;Verhagen MM et al, 2009;Silvestri G et al, 2010;Saunders-Pullman R et al, 2012;Verhagen MM et al, 2012;Worth PF et al, 2013;Claes K et al, 2013;M+ACY-eacute;neret A et al, 2014;Nakamura K et al, 2014;Gilad S et al, 1998).…”