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Brain Res. 2018 Aug 15;1693(Pt A):43-54. doi: 10.1016/j.brainres.2018.02.006. Epub 2018 Feb 14.

Repeat-associated non-AUG (RAN) translation and other molecular mechanisms in Fragile X Tremor Ataxia Syndrome.

Author information

1
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
2
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Veteran's Affairs Medical Center, Ann Arbor, MI 48105, USA.
3
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
4
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France. Electronic address: sellier@igbmc.fr.

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and dementia associated with mild brain atrophy. The cause of FXTAS is a premutation expansion, of 55 to 200 CGG repeats localized within the 5'UTR of FMR1. These repeats are transcribed in the sense and antisense directions into mutants RNAs, which have increased expression in FXTAS. Furthermore, CGG sense and CCG antisense expanded repeats are translated into novel proteins despite their localization in putatively non-coding regions of the transcript. Here we focus on two proposed disease mechanisms for FXTAS: 1) RNA gain-of-function, whereby the mutant RNAs bind specific proteins and preclude their normal functions, and 2) repeat-associated non-AUG (RAN) translation, whereby translation through the CGG or CCG repeats leads to the production of toxic homopolypeptides, which in turn interfere with a variety of cellular functions. Here, we analyze the data generated to date on both of these potential molecular mechanisms and lay out a path forward for determining which factors drive FXTAS pathogenicity.

KEYWORDS:

FMR1; FXTAS; Microsatellite expansion; RAN translation; RNA gelation

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