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Ataxia‐telangiectasia: Mild neurological presentation despite null ATM mutation and severe cellular phenotype

2007; Wiley; Volume: 143A; Issue: 16 Linguagem: Inglês

10.1002/ajmg.a.31853

1552-4833

Neora Alterman, Aviva Fattal‐Valevski, Lilach Moyal, Thomas O. Crawford, Howard M. Lederman, Yael Ziv, Yosef Shiloh,

Cancer-related Molecular Pathways

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.