Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome

Neuron. 2017 Jan 18;93(2):331-347. doi: 10.1016/j.neuron.2016.12.016. Epub 2017 Jan 5.


Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5' UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.

Keywords: RAN translation; microsatellite expansion; near-cognate codon; neurodegeneration.

Publication types

  • Video-Audio Media

MeSH terms

  • Animals
  • Ataxia / genetics*
  • Ataxia / metabolism
  • Brain / metabolism
  • Brain / pathology
  • DNA-Binding Proteins / metabolism*
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / metabolism
  • Humans
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Nuclear Lamina / metabolism*
  • Nuclear Lamina / pathology
  • Peptides / genetics*
  • Peptides / metabolism
  • Protein Biosynthesis*
  • RNA, Messenger / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Tremor / genetics*
  • Tremor / metabolism
  • Trinucleotide Repeat Expansion / genetics*


  • DNA-Binding Proteins
  • FMR1 protein, human
  • Membrane Proteins
  • Peptides
  • RNA, Messenger
  • lamina-associated polypeptide 2
  • Fragile X Mental Retardation Protein
  • polyglycine

Supplementary concepts

  • Fragile X Tremor Ataxia Syndrome