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8-ATM - review review ATM and ataxia telangiectasia Second...

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EMBO reports VOL 5 | NO 8 | 2004 ©2004 EUROPEAN MOLECULAR BIOLOGY ORGANIZATION 772 review review ATM and ataxia telangiectasia Second in Molecular Medicine Review Series Peter J. McKinnon St Jude Children’s Research Hospital, Memphis, Tennessee, USA Ataxia telangiectasia (AT) has long intrigued the biomedical research community owing to the spectrum of defects that are characteristic of the disease, including neurodegeneration, immune dysfunction, radiosensitivity and cancer predisposition. Following the identification of mutations in ATM (ataxia telangiectasia, mutated) as the underlying cause of the disease, biochemical analy- sis of this protein kinase has shown that it is a crucial nexus for the cellular response to DNA double-stranded breaks. Many ATM kinase substrates are important players in the cellular responses that prevent cancer. Accordingly, AT is a disease that results from defects in the response to specific types of DNA damage. Thus, although it is a rare neurodegenerative disease, understanding the biology of AT will lead to a greater understanding of the fundamental processes that underpin cancer and neurodegeneration. Keywords: ataxia telangiectasia; ATM; DNA damage; neuro- degeneration EMBO reports (2004) 5 , 772–776. doi:10.1038/sj.embor.7400210 Introduction Ataxia telangiectasia (AT) is a neurodegenerative disease that occurs early in childhood (Gatti et al , 2001; Sedgwick & Boder, 1991). Clinically, AT presents with uncoordinated or ataxic movements that are often associated with ocular telangiectasia (dilated blood vessels of the eye). One certain outcome of AT is that an individual will be wheelchair-bound early in life, almost always before the adolescent years. The prominent neurological sign of AT is an inexorable loss of cerebellar function, and pro- gressive dysarthria (speech defects) and choreoathetosis (abnor- mal body movements; Crawford, 1998; Gatti et al , 2001; Sedgwick & Boder, 1991). Autopsies and magnetic resonance imaging (MRI) studies have revealed significant thinning of the molecular layer of the cerebellum and cerebellar atrophy, espe- cially in vermal regions (Farina et al , 1994; Tavani et al , 2003). Characteristic eye movement abnormalities (distinct from telangiectasia) also feature strongly in AT, and these might be related to cerebellar dysfunction (Lewis et al , 1999). Although substantial advances have recently been made in the clinical diagnosis of this disease, treatments for the progressive neuro- degeneration are lacking (Perlman et al , 2003). In addition to the hallmark neurodegeneration, there are a num- ber of other features that typify this debilitating disease. These include immune dysfunction, sterility, radiosensitivity and lymphoid cancer (Fig 1). The immunodeficiency phenotype in AT is variable Department of Genetics and Tumor Cell Biology, St Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA Tel: +1 901 495 2700; Fax: +1 901 526 2907; E-mail: [email protected] Submitted 21 May 2004; accepted 23 June 2004 Neurodegeneration Immune defects Telangiectasia Radiosensitivity Sterility Cancer Fig 1 | Ataxia telangiectasia.Ataxia telangiectasia (AT) is a multisystem
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