TY - JOUR
T1 - Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: A genotype-phenotype study
AU - Verhagen, Mijke M. M.
AU - Last, James I.
AU - Hogervorst, Frans B. L.
AU - Smeets, Dominique F. C. M.
AU - Roeleveld, Nel
AU - Verheijen, Frans
AU - Catsman-Berrevoets, Coriene E.
AU - Wulffraat, Nico M.
AU - Cobben, Jan M.
AU - Hiel, Johan
AU - Brunt, Ewout R.
AU - Peeters, Els A. J.
AU - Gomez Garcia, Encarna B.
AU - van der Knaap, Marjo S.
AU - Lincke, Carsten R.
AU - Laan, Laura A. E. M.
AU - Tijssen, Marina A. J.
AU - van Rijn, Monique A.
AU - Majoor-Krakauer, Danielle
AU - Visser, Marjan
AU - van 't Veer, Laura J.
AU - Kleijer, Wim J.
AU - van de Warrenburg, Bart P. C.
AU - Warris, Adilia
AU - de Groot, Imelda J. M.
AU - de Groot, Ronald
AU - Broeks, Annegien
AU - Preijers, Frank
AU - Kremer, Berry H. P. H.
AU - Weemaes, Corry M. R.
AU - Taylor, Malcolm A. M. R.
AU - van Deuren, Marcel
AU - Willemsen, Michel A. A. P.
PY - 2012/3
Y1 - 2012/3
N2 - 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.
AB - 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.
KW - ataxia-telangietasia
KW - AT
KW - genotype-phenotype
KW - cancer
KW - ATM
U2 - 10.1002/humu.22016
DO - 10.1002/humu.22016
M3 - Article
C2 - 22213089
SN - 1059-7794
VL - 33
SP - 561
EP - 571
JO - Human Mutation
JF - Human Mutation
IS - 3
ER -