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Molecular Pathogenesis of Fragile X-Associated Tremor/Ataxia Syndrome
  1. Christopher Raske, MS,
  2. Paul J. Hagerman, MD, PhD
  1. From the Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA.
  1. Received July 10, 2009.
  2. Accepted for publication August 23, 2009.
  3. Reprints: Paul J. Hagerman, MD, PhD, Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA 95616. E-mail: pjhagerman{at}ucdavis.edu.
  4. Supported by the National Institute of Child Health and Development (R01 HD40661), the National Institute on Aging (RL1 AG32119), and an NIH Roadmap Interdisciplinary Research Consortium award (NIDCR UL1 DE19583), and the symposium was supported in part by a grant from the National Center for Research Resources (R13 RR023236).

Abstract

Fragile X-associated tremor/ataxia syndrome is a late adult onset neurodegenerative disorder that affects individuals who carry a premutation CGG repeat expansion (55-200 CGG repeats) in the 5′ untranslated portion of the fragile X mental retardation 1 (FMR1) gene. Affected individuals display cognitive decline, progressive intention tremor, gait ataxia, neuropathy, psychiatric symptoms, and parkinsonism; the severity of both clinical and neuropathological phenotypes is positively correlated with the extent of the CGG expansion. Overexpression of the expanded CGG repeat messenger RNA results in a direct gain-of-function cellular toxicity that is believed to form the pathogenic basis for fragile X-associated tremor/ataxia syndrome. This mechanism is entirely different from the mechanism giving rise to fragile X syndrome, which is due to transcriptional silencing and consequent loss of FMR1 protein. Much of the research in the field has focused on understanding the link between the pathogenic FMR1 messenger RNA and the potential proteins that interact with it.

Key Words
  • neurodegeneration
  • fragile X
  • autism
  • neuropathy
  • trinucleotide
  • CGG

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