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

被引:41
作者
Alterman, Neora
Fattal-Valevski, Aviva
Moyal, Lilach
Crawford, Thomas O.
Lederman, Howard M.
Ziv, Yael
Shiloh, Yosef [1 ]
机构
[1] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, David & Inez Myers Lab Genet Res, IL-69978 Tel Aviv, Israel
[2] Dana Childrens Hosp, Tel Aviv Sourasky Med Ctr, Inst Child Dev, Tel Aviv, Israel
[3] Dana Childrens Hosp, Tel Aviv Sourasky Med Ctr, Pediat Neurol Uint, Tel Aviv, Israel
[4] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD USA
[5] Johns Hopkins Univ, Sch Med, Div Pediat Allergy & Immunol, Baltimore, MD USA
关键词
ataxia-telangiectasia (A-T); mild A-T; A-T-like disease; cerebellar degeneration; ATM; DNA damage response;
D O I
10.1002/ajmg.a.31853
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive nettrodegeneration, 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 hontozygous for a truncating ATM mutation (5653delA) that is expected to lead 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. (C) 2007 Wiley-Liss, Inc.
引用
收藏
页码:1827 / 1834
页数:8
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