Repeat-Associated Non-ATG Translation in DM1 and DM2 (Project 1)- Ranum Well-established rules of translational initiation have been used as a cornerstone in molecular biology to understand gene expression and to predict the consequences of disease causing mutations. For myotonic dystrophy (DM) and other microsatellite expansion disorders, repeat expansions (e.g., CAG or CTGs) located in 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 2001, we showed that myotonic dystrophy type 2 (DM2) is caused by an intronic CCTG*CAGG expansion in CNBP. The apparent non-coding locations of the DM1 and DM2 expansion mutations and the accumulation of RNA foci in both disorders helped to establish that CUGEXP and CCUGEXP RNAs cause dominant RNA effects. While substantial data support RNA gain-of-function contributions to DM, recent discoveries, which fundamentally change our understanding of how disease-causing mutations are expressed, must also now be considered. First, much of the genome is bidirectionally transcribed, including the DM1 CTG'CAG expansion. Therefore, in addition to DM1 CUGEXP transcripts, mutant DM1 CAGEXP transcripts may also play a role in disease. Second, we recently discovered that the canonical rules of translation do not apply for CTG?CAG repeat expansions and that CAG and CUG expansion transcripts can express homopolymeric expansion proteins in all three frames without an AUG start codon. This Repeat-Associated Non-ATG (RAN) translation is hairpin dependent, occurs without frameshifting or RNA editing and is observed in cell culture and DMpatient tissues. We propose to test the overall hypothesis that RAN translation contributes to DM disease pathogenesis.
Our specific aims are to test the hypotheses: 1) that novel polymeric expansion proteins expressed by RAN translation accumulate in DM1 and DM2 brain and contribute to CNS pathology;2) that RAN proteins are toxic independent of RNA gain of function effects;3) that RAN translation can be blocked in vivo.

Public Health Relevance

We have discovered a new translational mechanism in which disease-causing repeats in DNA direct the expression of an unexpected category of proteins without the normal regulatory signals. The goals of this project are to understand if these mutant proteins are toxic to cells and if they contribute to myotonic dystrophy types 1 and 2. These studies have potential relevance to >30 microsatellite expansion diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
United States
Zip Code
Taliaferro, J Matthew; Vidaki, Marina; Oliveira, Ruan et al. (2016) Distal Alternative Last Exons Localize mRNAs to Neural Projections. Mol Cell 61:821-33
Freyermuth, Fernande; Rau, Frédérique; Kokunai, Yosuke et al. (2016) Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat Commun 7:11067
Scotti, Marina M; Swanson, Maurice S (2016) RNA mis-splicing in disease. Nat Rev Genet 17:19-32
Goodwin, Marianne; Mohan, Apoorva; Batra, Ranjan et al. (2015) MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain. Cell Rep 12:1159-68
Hewitt, Angela L; Popa, Laurentiu S; Ebner, Timothy J (2015) Changes in Purkinje cell simple spike encoding of reach kinematics during adaption to a mechanical perturbation. J Neurosci 35:1106-24
Coram, Ryan J; Stillwagon, Samantha J; Guggilam, Anuradha et al. (2015) Muscleblind-like 1 is required for normal heart valve development in vivo. BMC Dev Biol 15:36
Xia, Guangbin; Gao, Yuanzheng; Jin, Shouguang et al. (2015) Genome modification leads to phenotype reversal in human myotonic dystrophy type 1 induced pluripotent stem cell-derived neural stem cells. Stem Cells 33:1829-38
Batra, Ranjan; Manchanda, Mini; Swanson, Maurice S (2015) Global insights into alternative polyadenylation regulation. RNA Biol 12:597-602
Davis, Jennifer; Salomonis, Nathan; Ghearing, Natasha et al. (2015) MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response. Nat Commun 6:10084
Rau, Frédérique; Lainé, Jeanne; Ramanoudjame, Laetitita et al. (2015) Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. Nat Commun 6:7205

Showing the most recent 10 out of 47 publications