The molecular biology of premutation expanded alleles

Flora Tassone, Chantal Sellier, Nicolas Charlet-Berguerand, Peter K. Todd

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult onset neurodegenerative disorder that mainly affects male carriers of an allele of 55-200 CGG repeats in the FMR1 gene (premutation). FXTAS symptoms include progressive intention tremor, gait ataxia, neuropathy, psychiatric symptoms, cognitive decline, and autonomic dysfunctions. Neuropathological features of FXTAS include global cerebral and cerebellar atrophy, spongiform changes of white matter, marked Purkinje cell dropout and presence of ubiquitin-positive intranuclear inclusions throughout the brain. In contrast to fragile X Syndrome (FXS), FXTAS is associated with elevated expression of repeat containing FMR1 mRNA, which binds to and sequesters specific RNA binding proteins and impedes their normal functions. In addition, the CGG repeat expansion triggers a non-canonical translational initiation event to produce a polyglycine containing protein (FMRpolyG) that accumulates in patients brains. Here we discuss these and other putative molecular mechanisms for FXTAS pathogenesis with a focus on recent findings.

Original languageEnglish (US)
Title of host publicationFXTAS, FXPOI, and Other Premutation Disorders
PublisherSpringer International Publishing
Pages101-127
Number of pages27
ISBN (Electronic)9783319338989
ISBN (Print)9783319338965
DOIs
StatePublished - Jan 1 2016

Keywords

  • Antisense
  • Disease mechanisms
  • Neurodegenerative disease
  • RAN translation
  • RNA disease
  • Transcription

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Neuroscience(all)

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  • Cite this

    Tassone, F., Sellier, C., Charlet-Berguerand, N., & Todd, P. K. (2016). The molecular biology of premutation expanded alleles. In FXTAS, FXPOI, and Other Premutation Disorders (pp. 101-127). Springer International Publishing. https://doi.org/10.1007/978-3-319-33898-9_6