CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome

Judith R. Brouwer, Karin Huizer, Lies Anne Severijnen, Renate K. Hukema, Robert F Berman, Ben A. Oostra, Rob Willemsen

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


The 5′untranslated region (UTR) of the FMR1 gene contains a CGG-repeat, which may become unstable upon transmission to the next generation. When repeat length exceeds 200, the FMR1 gene generally undergoes methylation-mediated transcriptional silencing. The subsequent absence of the gene product Fragile X Mental Retardation Protein (FMRP)causes the mental retardation seen in fragile X patients. A CGG-repeat length between 55 and 200 trinucleotides has been termed the premutation (PM). Predominantly elderly male PM carriers are at risk of developing a progressive neurodegenerative disorder: fragile X-associated tremor/ataxia syndrome (FXTAS). All PM carriers have elevated FMR1 mRNA levels, in spite of slightly decreased FMRP levels. The presence of intranuclear ubiquitin-positive inclusions in many brain regions is a neuropathological hallmark of FXTAS. Studies in humans attempting to correlate neuropathological outcomes with molecular measures are difficult because of the limited availability of tissue. Therefore, we have used the expanded CGG-repeat knock-in mouse model of FXTAS to examine the relationship between the molecular and neuropathological parameters in brain. We present Fmr1 mRNA and Fmrp levels and the presence of intranuclear inclusions at different repeat lengths. Contrary to existing hypotheses, our results suggest that inclusion formation may not depend on the elevation per se of Fmr1 transcript levels in aged CGG mice.

Original languageEnglish (US)
Pages (from-to)1671-1682
Number of pages12
JournalJournal of Neurochemistry
Issue number6
StatePublished - Dec 2008


  • CGG repeat
  • Fmr1
  • FMRP
  • Fragile X-associated tremor/ataxia syndrome
  • Inclusions
  • RNA gain-of-function

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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