title: Ataxia-telangiectasia: mild neurological presentation despite null ATM mutation and severe cellular phenotype.
abstract: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive neurodegeneration, immunodeficiency, susceptibility to cancer, genomic instability, and sensitivity to ionizing radiation. A-T is caused by mutations that eliminate or inactivate the nuclear protein kinase ATM, the chief activator of the cellular response to double strand breaks (DSBs) in the DNA. Mild A-T is usually caused by ATM mutations that leave residual amounts of active ATM. We studied two siblings with mild A-T, as defined by clinical examination and a quantitative A-T neurological index. Surprisingly, no ATM was detected in the patients' cells, and sequence analysis revealed that they were homozygous for a truncating ATM mutation (5653delA) that is expected to lead to the classical, severe neurological presentation. Moreover, the cellular phenotype of these patients was indistinguishable from that of classical A-T: all the tested parameters of the DSB response were severely defective as in typical A-T. This analysis shows that the severity of the neurological component of A-T is determined not only by ATM mutations but also by other influences yet to be found.
authors.affiliation: The David and Inez Myers Laboratory for Genetic Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Neora
authors.initials: N
authors.lastname: Alterman
authors.forename: Aviva
authors.initials: A
authors.lastname: Fattal-Valevski
authors.forename: Lilach
authors.initials: L
authors.lastname: Moyal
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Crawford
authors.forename: Howard M
authors.initials: HM
authors.lastname: Lederman
authors.forename: Yael
authors.initials: Y
authors.lastname: Ziv
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shiloh
mesh_terms: D001260:Ataxia Telangiectasia / Q000175:diagnosis* / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: 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