Repeat expansion disease: progress and puzzles in disease pathogenesis

Nat Rev Genet. 2010 Apr;11(4):247-58. doi: 10.1038/nrg2748.


Repeat expansion mutations cause at least 22 inherited neurological diseases. The complexity of repeat disease genetics and pathobiology has revealed unexpected shared themes and mechanistic pathways among the diseases, such as RNA toxicity. Also, investigation of the polyglutamine diseases has identified post-translational modification as a key step in the pathogenic cascade and has shown that the autophagy pathway has an important role in the degradation of misfolded proteins--two themes that are likely to be relevant to the entire neurodegeneration field. Insights from repeat disease research are catalysing new lines of study that should not only elucidate molecular mechanisms of disease but also highlight opportunities for therapeutic intervention for these currently untreatable disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Ataxia / genetics
  • Ataxin-1
  • Ataxins
  • Autophagy / genetics
  • DNA Repeat Expansion*
  • Fragile X Syndrome / genetics
  • Humans
  • Huntingtin Protein
  • Mice
  • Myotonic Dystrophy / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nervous System Diseases / etiology
  • Nervous System Diseases / genetics*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Peptides / genetics
  • Protein Processing, Post-Translational
  • RNA / genetics
  • RNA / toxicity
  • Spinocerebellar Degenerations / genetics


  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • Atxn1 protein, mouse
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • polyglutamine
  • RNA

Supplementary concepts

  • Spinocerebellar ataxia 8