Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.
SourceHuman Mutation, 33, 3, (2012), pp. 561-71
01 maart 2012
Article / Letter to editor
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Paediatrics - OUD tm 2017
Laboratory of Hematology
Epidemiology, Biostatistics & HTA
SubjectDCN MP - Plasticity and memory; N4i 1: Pathogenesis and modulation of inflammation; N4i 2: Invasive mycoses and compromised host; NCEBP 10: Human Movement & Fatigue DCN PAC - Perception action and control; NCEBP 12: Human Reproducion IGMD 3: Genomic disorders and inherited multi-system disorders; NCEBP 6: Quality of nursing and allied health care; NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders; ONCOL 3: Translational research
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 genotype-phenotype 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.
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