Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: A genotype-phenotype study

MMM Verhagen, JI Last, FBL Hogervorst, DFCM Smeets, N Roeleveld, Frans Verheijen, Coriene Catsman - Berrevoets, NM Wulffraat, JM Cobben, J Hiel, ER Brunt, EAJ Peeters, EBG Garcia, MS van der Knaap, CR Lincke, LAEM Laan, MAJ Tijssen, MA (M.) van Rijn, Danielle Majoor - Krakauer, Martje VisserLJ (Laura) van 't Veer, WJ (Wim) Kleijer, BPC van de Warrenburg, A Warris, IJM de Groot, Ronald Groot, A Broeks, F Preijers, BHPH Kremer, CMR Weemaes, MAMR Taylor, M van Deuren, MAAP Willemsen

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Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotypephenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk. Hum Mutat 33:561571, 2012. (C) 2011 Wiley Periodicals, Inc.
Original languageUndefined/Unknown
Pages (from-to)561-571
Number of pages11
JournalHuman Mutation
Issue number3
Publication statusPublished - 2012

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