Medline ® Abstract for Reference 71
Ataxia-telangiectasia: mild neurological presentation despite null ATM mutation and severe cellular phenotype.
Alterman N, Fattal-Valevski A, Moyal L, Crawford TO, Lederman HM, Ziv Y, Shiloh Y
Am J Med Genet A. 2007;143A(16):1827.
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.
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.