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New developments in RAN translation: insights from
multiple diseases
1,2,4 1,2,3,4,5
John Douglas Cleary and Laura PW Ranum
Since the discovery of repeat-associated non-ATG (RAN) expanded repeats is capable of producing a startling array
translation, and more recently its association with amyotrophic of toxic expansion proteins. Here we focus on recent
lateral sclerosis/frontotemporal dementia, there has been an developments in RAN translation, its mechanistic under-
intense focus to understand how this process works and the pinnings and efforts to understand the impact of RAN
downstream effects of these novel proteins. RAN translation proteins in neurologic disease.
across several different types of repeat expansions mutations
(CAG, CTG, CCG, GGGGCC, GGCCCC) results in the RAN translation and the resulting toxic homopolymeric
production of proteins in all three reading frames without an proteins were first described in spinocerebellar ataxia
ATG initiation codon. The combination of bidirectional type 8 and myotonic dystrophy type 1 [1]. This discovery
transcription and RAN translation has been shown to result in was followed by descriptions of homopolymeric RAN
the accumulation of up to six mutant expansion proteins in a proteins in fragile X tremor ataxia syndrome (FXTAS)
growing number of diseases. This process is complex [3] and dipeptide RAN proteins in C9of72 amyotrophic
mechanistically and also complex from the perspective of the lateral sclerosis (ALS)/frontotemporal dementia (FTD)
downstream consequences in disease. Here we review recent [4–8]. While research on the effects of RAN dipeptide
developments in RAN translation and their implications on our repeat (DPR) proteins in C9-ALS/FTD has produced
basic understanding of neurodegenerative disease and gene the largest amount of data and interest to date, RAN
expression. translation has been observed in other diseases and
interest in its impact and mechanisms is growing Addresses
1 (Figure 1).
Center for NeuroGenetics, University of Florida, Gainesville, FL, USA
2
Department of Molecular Genetics & Microbiology, College of
Medicine, University of Florida, Gainesville, FL, USA
3 RAN proteins in Huntington disease and other
Department of Neurology, University of Florida, Gainesville, FL, USA
4 polyglutamine disorders
Genetics Institute, University of Florida, Gainesville, FL, USA
5
McKnight Brain Institute, University of Florida, Gainesville, FL, USA Huntington disease (HD), a progressive neurodegenera-
tive disorder characterized by severe movement, cogni-
Corresponding author: Ranum, Laura PW (ranum@ufl.edu)
tive and behavioral alterations, is caused by a CAG CTG
expansion in the HTT gene [9]. The mutant huntingtin
mHTT protein, which contains a polyglutamine expan-
Current Opinion in Genetics & Development 2017, 44:125–134
sion tract, is expressed from the sense-strand as part of a
This review comes from a themed issue on Molecular and genetic
large ATG-initiated open reading frame (ORF). While it
bases of disease
is clear that the HD CAG CTG expansion mutation
Edited by Nancy M Bonini, Edward B Lee, Wilma Wasco and Allen
Roses causes disease [10], HD research has almost exclusively
been focused on the mutant huntingtin (mHTT) poly-
For a complete overview see the Issue and the Editorial
glutamine expansion protein because it was thought to be
Available online 30th March 2017
the only mutant protein that could be expressed across
http://dx.doi.org/10.1016/j.gde.2017.03.006 the expansion mutation. The first examples of RAN
0959-437X/ã 2017 Elsevier Ltd. All rights reserved. translation were found to occur across expansion muta-
tions located in non-coding gene regions (SCA8, DM1,
C9orf72 ALS/FTD, and FXTAS). Because the HD
expansion is much smaller and is located within a large
canonical ORF that could inhibit RAN translation, it was
unclear if RAN translation could also occur across the HD
An expanding field: updates on RAN- mutation.
associated disorders