Disease Progression in Myotonic Dystrophy Research on myotonic dystrophy type 1 (DM1) has led to the recognition of a new paradigm for muscle disease. The mutation in DM1, an expanded CTG repeat in the 3'untranslated region of DMPK, is unstable in somatic cells. The expansion continues to increase in size in muscle cells during postnatal life, reaching lengths of several thousand repeats. The mechanisms underlying this unusual genetic behavior, and the relationships among increasing repeat length and onset or progression of DM1, have not been determined. Deleterious effects of the mutation are mediated by the mutant RNA, which contains an expanded CUG repeat (CUGexp). Recent findings in transgenic mouse models have identified several cellular pathways that are affected by CUGexp RNA, such as, MBNL1 sequestration and upregulation of CUGBP1 or NKX2.5. However, which of these mechanisms are primarily responsible for muscle degeneration in human DM1 is in question. This multifaceted project brings together a large collaborative team to study the mechanisms for repeat instability and the relationships among CTG repeat length, biochemical changes, and muscle impairment in individuals with DM1. Our goal is to focus therapeutic effort on the targets that are most pertinent to DM1 progression. Studies of pathogenesis will be tightly coordinated with prospective longitudinal follow up in a cohort of individuals with DM1. The goal of this analysis is to define rates of DM1 progression and determine which outcomes are most sensitive for monitoring disease progression and suitable as endpoints in clinical trials.
Aim 1 employs a new method for cell free cloning of CTG repeats to study the effects of cell division, genomic position, transcription, and oxidative damage on stability of highly expanded CTG repeats in human cells.
Aim 2 examines the relationships among repeat length, biochemical changes, and weakness in the same muscle.
Aim 3 compares loss of muscle bulk and strength over time with functional impairments that are characterstic of DM1. Overall, this project will supply critical information that is needed to move forward with therapeutic development in DM1.
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