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)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of Florida
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