Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study
| Autor: | Mijke M. M. Verhagen, James I. Last, Frans B. L. Hogervorst, Dominique F. C. M. Smeets, Nel Roeleveld, Frans Verheijen, Coriene E. Catsman-Berrevoets, Nico M. Wulffraat, Jan M. Cobben, Johan Hiel, Ewout R. Brunt, Els A. J. Peeters, Encarna B. Gómez Garcia, Marjo S. van der Knaap, Carsten R. Lincke, Laura A. E. M. Laan, Marina A. J. Tijssen, Monique A. van Rijn, Danielle Majoor-Krakauer, Marjan Visser, Laura J. van 't Veer, Wim J. Kleijer, Bart P. C. van de Warrenburg, Adilia Warris, Imelda J. M. de Groot, Ronald de Groot, Annegien Broeks, Frank Preijers, Berry H. P. H. Kremer, Corry M. R. Weemaes, Malcolm A. M. R. Taylor, Marcel van Deuren, Michèl A. A. P. Willemsen |
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| Přispěvatelé: | ANS - Amsterdam Neuroscience, Other Research, Human Genetics, Paediatric Genetics, Other departments, Psychiatrie & Neuropsychologie, KNO, RS: GROW - School for Oncology and Reproduction, Molecular Neuroscience and Ageing Research (MOLAR), Clinical Genetics, Neurology, Pharmacy, Pediatric Surgery, Medical Microbiology & Infectious Diseases, Nutrition and Health, Neuroscience Campus Amsterdam - Childhood White Matter Diseases, Internal Medicine Specializations, Human genetics, Pediatric surgery, NCA - Childhood White Matter Diseases |
| Rok vydání: | 2011 |
| Předmět: |
Male
FEATURES RECOMBINATION Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins LYMPHOMA Missense mutation Child Genetics (clinical) RISK Splice site mutation GERMLINE MUTATIONS Middle Aged Phenotype Human Movement & Fatigue DCN PAC - Perception action and control [NCEBP 10] genotype-phenotype Pathogenesis and modulation of inflammation [N4i 1] 5762INS137 DNA-Binding Proteins Female Adult NIJMEGEN BREAKAGE SYNDROME Adolescent DCN MP - Plasticity and memory Quality of nursing and allied health care [NCEBP 6] Biology Protein Serine-Threonine Kinases Invasive mycoses and compromised host [N4i 2] Ataxia Telangiectasia Young Adult Germline mutation SDG 3 - Good Health and Well-being Translational research [ONCOL 3] Genetics medicine cancer BREAST-CANCER Humans Kinase activity Genetic Association Studies BRITISH-ISLES Tumor Suppressor Proteins Human Reproducion Genomic disorders and inherited multi-system disorders [NCEBP 12] medicine.disease GENE ATM Immunology Ataxia-telangiectasia Cancer research AT ataxia-telangietasia Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6] Nijmegen breakage syndrome |
| Zdroj: | Human mutation, 33(3), 561-571. Wiley-Liss Inc. Human Mutation, 33(3), 561-571. Wiley Human Mutation, 33, 3, pp. 561-71 Verhagen, M M M, Last, J I, Hogervorst, F B L, Smeets, D F C M, Roeleveld, N, Verheijen, F, Catsman-Berrevoets, C E, Wulffraat, NM, Cobben, J M, Hiel, J, Brunt, E R, Peeters, E A J, Garcia, E B G, van der Knaap, M S, Lincke, C R, Laan, L A E M, Tijssen, M A J, van Rijn, M A, Majoor-Krakauer, D, Visser, M, van 't Veer, L J, Kleijer, W J, van de Warrenburg, B P C, Warris, A, de Groot, I J M, de Groot, R, Broeks, A, Preijers, F, Kremer, B H P H, Weemaes, C M R, Taylor, M A M R, van Deuren, M & Willemsen, M A A P 2012, ' Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: A genotype-phenotype study ', Human Mutation, vol. 33, no. 3, pp. 561-571 . https://doi.org/10.1002/humu.22016 Human Mutation, 33, 561-71 Human Mutation, 33(3), 561-571. Wiley-Liss Inc. |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.22016 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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