Genetic models of C9orf72: what is toxic?

Curr Opin Genet Dev. 2017 Jun;44:92-101. doi: 10.1016/j.gde.2017.01.006. Epub 2017 Mar 29.


A hexanucleotide repeat expansion in the gene C9orf72 is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Pathogenesis may occur either due to loss of function of the C9orf72 gene, or a toxic gain of function, via the production of repetitive sense and antisense RNA and/or repetitive dipeptide repeat proteins. Recently, mouse knockouts have suggested that a loss of function of C9orf72 alone is insufficient to lead to neurodegeneration, whilst overexpression of hexanucleotide DNA is sufficient in a wide range of model systems. Additionally, models have now been created to attempt to study the effects of repetitive RNA and dipeptide proteins in isolation and thus determine their relevance to disease.

Publication types

  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • C9orf72 Protein / genetics*
  • Dipeptides / genetics
  • Disease Models, Animal
  • Frontotemporal Dementia / genetics*
  • Frontotemporal Dementia / pathology
  • Humans
  • Mice
  • Mice, Knockout / genetics
  • Nerve Degeneration / genetics*
  • Nerve Degeneration / pathology
  • Repetitive Sequences, Amino Acid / genetics


  • C9orf72 Protein
  • C9orf72 protein, human
  • Dipeptides