# Biological determinants of myotonic dystrophy variability

> **NIH NIH P50** · UNIVERSITY OF FLORIDA · 2024 · $361,440

## Abstract

Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in exon 15 of DMPK, whereas myotonic
dystrophy type 2 (DM2) is caused by expanded CCTG repeats in intron 1 of CNPB. DM1 and DM2 are the first
genetic diseases recognized to result from RNA toxicity, a complex process that reflects an interplay of
synthesis and turnover of expanded RNA repeats, and phase separation of repeat RNA and binding proteins in
nuclear condensates, or foci. DM1 is one of the most variable genetic diseases known to medicine, where onset
can occur at any time from mid-gestation to 7th decade. The DM1 expanded repeat is genetically unstable,
resulting in a wide range of different repeat lengths. Clinical variability of DM1 was attributed to differences of
repeat length, reflecting repeats that a person inherits (progenitor allele length) and additional length that
arises through somatic expansion, an age-dependent growth which occurs at different rates in different tissues.
Initial studies indicated that clinical variability is mainly attributable to progenitor allele length, but this was
not confirmed in recent studies. Further, the severity of involvement in individual muscles is not associated
with repeat length in tissue: all adult DM1 patients show large expansions in muscle, regardless of whether the
muscle is heavily affected or not. Here we will re-assess the association of repeat length with disease severity,
using a new platform for clinical assessment, remote study visits (RSVs), and a new molecular assay for repeat
length. We posit that while somatic expansion is necessary for DM1 onset and progression, and occurs in all
patients, it does not account for between-patient variability. Instead, we postulate that clinical variability
reflects differences in how large expansions manifest as RNA toxicity. Discovering the genetic determinants of
these differences, which are currently unknown, will require genome-wide unbiased analyses. First, however, it
is necessary to clarify the predictive value of repeat length, determine the residual variance that is not
attributable to repeat length, and establish new methods to assemble large cohorts and analyze their repeat
lengths, as proposed here in a cohort of 600 patients. We also will investigate the mechanisms for RNA toxicity
in DM2, which has added complexity that repeats are very large and located in an intron. We will focus on
aspects of DM2 that are most critical for selecting an effective therapeutic approach: 1) is the expanded CCUG-
repeat RNA causing toxicity an excised intron that is actively undergoing degradation, or a retained intron in
the CNBP mRNA; and (2) does the repeat RNA undergo repeat-associated non-AUG (RAN) translation in
muscle. Resolving these questions is critical to ensure that therapeutic strategies that are now in clinical trials
for DM1 can be safely and effectively applied to DM2. Taken together, the proposed studies will clarify the
genetic determinants of DM1 severity, impro...

## Key facts

- **NIH application ID:** 10992318
- **Project number:** 1P50NS132955-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Johanna I Hamel
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $361,440
- **Award type:** 1
- **Project period:** 2024-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10992318

## Citation

> US National Institutes of Health, RePORTER application 10992318, Biological determinants of myotonic dystrophy variability (1P50NS132955-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10992318. Licensed CC0.

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