title: Repeat-associated non-ATG (RAN) translation in neurological disease.
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.
authors.forename: John D
authors.initials: JD
authors.lastname: Cleary
authors.forename: Laura P W
authors.initials: LP
authors.lastname: Ranum
mesh_terms: D000073885:C9orf72 Protein; D018387:Codon, Initiator; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D065636:Myotonin-Protein Kinase; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009422:Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016366:Open Reading Frames; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017393:RNA Editing; D019680:Trinucleotide Repeat Expansion
chemical_list: D000073885:C9orf72 Protein; D018387:Codon, Initiator; D051860:Fragile X Messenger Ribonucleoprotein 1; D050505:Mutant Proteins; D065636:Myotonin-Protein Kinase; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; C568651:C9orf72 protein, human; C585517:DMPK protein, human; C497683:FMR1 protein, human
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