Ataxia telangiectasia

doi:10.1017/CBO9780511544873.050

49 - Ataxia telangiectasia

from Part VIII - Cerebellar degenerations

Published online by Cambridge University Press: 04 August 2010

Anthony E. Lang and

Susan Perlman and

M. Flint Beal: Affiliation:
Cornell University, New York
Anthony E. Lang: Affiliation:
University of Toronto
Albert C. Ludolph: Affiliation:
Universität Ulm, Germany
Richard A. Gatti: Affiliation:
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Tom O. Crawford: Affiliation:
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Alan S. Mandir: Affiliation:
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Susan Perlman: Affiliation:
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Howard T. J. Mount: Affiliation:
CRND, Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada

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Summary

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder associated with abnormal function of the nervous, immune and endocrine systems. It was initially described by Syllaba and Henner (1926) and was more completely characterized by Boder and Sedgwick (1958), who also coined the name. The disorder is characterized by a progressive gait and truncal ataxia, immunodeficiency, thymic degeneration, chromosomal instability, predisposition to lymphoreticular malignancies and hypersensitivity to ionizing radiation (for review see Boder, 1985; Gatti et al., 1991; Sedgwick & Boder, 1991; Woods & Taylor, 1992; Gatti, 2002).

Early research into the genetic cause of A-T suggested the presence of as many as four different responsible genes since fusion of fibroblasts from various A-T patients were able to complement one another in radiation sensitivity assays (Jaspers et al., 1988). However, all four groups were subsequently found to have loss-of-function mutations in a single gene, named ATM (ataxia-telangiectasia mutated), located on chromosome 11q22.3 (Gatti et al., 1988; Savitsky et al., 1995).

The ATM protein is a serine/threonine kinase responsible for maintaining genomic integrity by triggering arrest of the cell cycle, increasing transcription of stress response genes, and repair of double strand breaks in DNA (Shiloh, 2003). Among the many identified substrates are p53, p53BP, MDM2, Chk2, nibrin, Mre11, H2AX, SMC1, Pin2/TRF1, FANCD2, MDC1, and BRCA1. A-T patients express a functionally deficient ATM message, with diminished or absent levels of ATM protein (Chun et al., 2003). How mutations in ATM result in radiation hypersensitivity or neuronal integrity remains unclear.

Type: Chapter
Information: Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics
, pp. 738 - 748

DOI: https://doi.org/10.1017/CBO9780511544873.050 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2005

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