# Repeat Associated non-AUG translation in Myotonic Dystrophy Type 1

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2022 · $33,882

## Abstract

Abstract
Myotonic dystrophy type 1 (DM1) is the leading cause of adult-onset muscular dystrophy and a
member of the large family of over 40+ repeat expansions diseases. In 2011, the Ranum lab
discovered that many of these expansion mutations can express repetitive proteins without an
AUG initiation codon using a novel process called repeat associated non-AUG (RAN)
translation. In this initial study, it was demonstrated that the DM1 antisense CAG expansion
transcripts express RAN proteins with the antisense RAN polyGln proteins accumulating in
disease relevant tissue of DM1 patient and mouse models. While this initial data suggested that
RAN proteins might contribute to DM1, the tools and techniques to detect RAN proteins at the
time were not sufficiently sensitive to allow for a thorough examination of the role of RAN
proteins in DM1. One important unanswered question is the potential role of RAN proteins in the
CNS abnormalities of DM1, which have been shown to significantly impact quality of life. Novel
and specific RAN protein immunological detection tools newly developed by the Ranum group
shows that frequent the DM1 RAN proteins, polyLeu (sense transcript) and polySer, (antisense
transcript) accumulate in neurons and glial cells in grey and white matter regions of DM1 frontal
cortex. The Ranum lab has also shown that the FDA-approved type 2 diabetes drug metformin
inhibits RAN translation and improved disease phenotypes in C9orf72 ALS/FTD mice (ref),
suggesting a similar approach may work in DM1. The central hypothesis of this proposal is that
RAN translation contributes to DM1 and that modulating RAN translation will mitigate disease
features. To test this hypothesis, we will: (1) determine if RAN protein aggregates accumulate in
DM1 brain regions that show neuroinflammation and other types of histopathology; (2) examine
sense and antisense RAN proteins accumulate in skeletal muscle and if RAN protein
accumulation increases with age and muscle pathology; and (3) assess if DM1 RAN proteins
are toxic and if inhibiting RAN translation with metformin will improve phenotypes in DM1 iPSC-
derived muscle and brain organoids. Taken together these studies will improve our
understanding of the role of RAN translation in DM1 and provide strong mechanistic rationale
for the use of metformin as a therapeutic strategy for DM1 patients.

## Key facts

- **NIH application ID:** 10526735
- **Project number:** 3R01NS117910-01A1S1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Monica Banez-Coronel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,882
- **Award type:** 3
- **Project period:** 2021-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526735

## Citation

> US National Institutes of Health, RePORTER application 10526735, Repeat Associated non-AUG translation in Myotonic Dystrophy Type 1 (3R01NS117910-01A1S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10526735. Licensed CC0.

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