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The Molecular Biology of Premutation Expanded Alleles

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FXTAS, FXPOI, and Other Premutation Disorders

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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.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA

    Flora Tassone

  2. MIND Institute, UC Davis Medical Center, Sacramento, CA, USA

    Flora Tassone

  3. IGBMC, CNRS UMR7104, INSERM U964, University of Strasbourg, Illkirch, France

    Chantal Sellier & Nicolas Charlet-Berguerand

  4. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Peter K. Todd

  5. VA Medical Center, Ann Arbor, MI, USA

    Peter K. Todd

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  1. Flora Tassone
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  1. Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA

    Flora Tassone

  2. Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA

    Deborah A. Hall

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Tassone, F., Sellier, C., Charlet-Berguerand, N., Todd, P.K. (2016). The Molecular Biology of Premutation Expanded Alleles. In: Tassone, F., Hall, D. (eds) FXTAS, FXPOI, and Other Premutation Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-33898-9_6

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