Repeat-associated non-ATG (RAN) translation in neurological disease

Hum Mol Genet. 2013 Oct 15;22(R1):R45-51. doi: 10.1093/hmg/ddt371. Epub 2013 Aug 4.

Abstract

Well-established rules of translational initiation have been used as a cornerstone in molecular biology to understand gene expression and to frame fundamental questions on what proteins a cell synthesizes, how proteins work and to predict the consequences of mutations. For a group of neurological diseases caused by the abnormal expansion of short segments of DNA (e.g. CAG•CTG repeats), mutations within or outside of predicted coding and non-coding regions are thought to cause disease by protein gain- or loss-of-function or RNA gain-of-function mechanisms. In contrast to these predictions, the recent discovery of repeat-associated non-ATG (RAN) translation showed expansion mutations can express homopolymeric expansion proteins in all three reading frames without an AUG start codon. This unanticipated, non-canonical type of protein translation is length-and hairpin-dependent, takes place without frameshifting or RNA editing and occurs across a variety of repeat motifs. To date, RAN proteins have been reported in spinocerebellar ataxia type 8 (SCA8), myotonic dystrophy type 1 (DM1), fragile X tremor ataxia syndrome (FXTAS) and C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). In this article, we review what is currently known about RAN translation and recent progress toward understanding its contribution to disease.

Publication types

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

MeSH terms

  • C9orf72 Protein
  • Codon, Initiator
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Gene Expression
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism*
  • Mutation
  • Myotonin-Protein Kinase
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nervous System Diseases / genetics*
  • Nervous System Diseases / metabolism
  • Nervous System Diseases / pathology
  • Open Reading Frames
  • Peptide Chain Initiation, Translational*
  • Protein Biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism
  • RNA Editing
  • Trinucleotide Repeat Expansion*

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Codon, Initiator
  • DMPK protein, human
  • FMR1 protein, human
  • Mutant Proteins
  • Nerve Tissue Proteins
  • Proteins
  • Fragile X Mental Retardation Protein
  • Myotonin-Protein Kinase
  • Protein-Serine-Threonine Kinases