Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.
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.
Department of Pediatric Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
Mijke M M
MM
Verhagen
James I
JI
Last
Frans B L
FB
Hogervorst
Dominique F C M
DF
Smeets
Nel
N
Roeleveld
Frans
F
Verheijen
Coriene E
CE
Catsman-Berrevoets
Nico M
NM
Wulffraat
Jan M
JM
Cobben
Johan
J
Hiel
Ewout R
ER
Brunt
Els A J
EA
Peeters
Encarna B
EB
Gómez Garcia
Marjo S
MS
van der Knaap
Carsten R
CR
Lincke
Laura A E M
LA
Laan
Marina A J
MA
Tijssen
Monique A
MA
van Rijn
Danielle
D
Majoor-Krakauer
Marjan
M
Visser
Laura J
LJ
van 't Veer
Wim J
WJ
Kleijer
Bart P C
BP
van de Warrenburg
Adilia
A
Warris
Imelda J M
IJ
de Groot
Ronald
R
de Groot
Annegien
A
Broeks
Frank
F
Preijers
Berry H P H
BH
Kremer
Corry M R
CM
Weemaes
Malcolm A M R
MA
Taylor
Marcel
M
van Deuren
Michèl A A P
MA
Willemsen
D000293:Adolescent; D000328:Adult; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases