Ataxia telangiectasia

Richard A. Gatti, Tom O. Crawford, Alan S. Mandir, Susan Perlman, Howard T.J. Mount

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

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.

Original languageEnglish (US)
Title of host publicationNeurodegenerative Diseases
Subtitle of host publicationNeurobiology, Pathogenesis and Therapeutics
PublisherCambridge University Press
Pages738-748
Number of pages11
ISBN (Electronic)9780511544873
ISBN (Print)052181166X, 9780521811668
DOIs
StatePublished - Jan 1 2005

ASJC Scopus subject areas

  • Medicine(all)

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