Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects

DESCRIPTION (provided by applicant): Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the DMPK gene. The identification and characterization of RNA-binding proteins that interact with expanded CUG repeats and the discovery that a similar CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2), have provided strong support that RNA gain of function effects play an important role in DM manifestations in skeletal muscle. Although the CNS deficits are one of the most clinically significant aspects of DM, the molecular mechanisms underlying these changes have been unclear. Progress during the current funding period extends our understanding of the CNS features of the disease and molecular mechanisms of microsatellite expansion mutations. Project #3 (PI: Day) has established that DM results in a striking diffuse abnormality of white matter integrity that parallels the cognitive deficits in children, and executive function deficits in adults. Project #2 (PI: Swanson) has extended our understanding of the role of RNA gain of function effects by demonstrating that another member of the MBNL gene family, MBNL2, is a critical regulator of alternative splicing during postnatal brain development. Project #1 (PI: Ranum) has made the unexpected discovery that microsatellite expansion mutations can express homopolymeric expansion proteins without the canonical AUG-initiation codon and that novel proteins accumulate in DM patient tissue. These results suggest novel expansion proteins contribute to DM. The focus of this proposal will be to better understand the clinical consequences of the DM1 and DM2 mutations and to relate specific clinical phenotypes to underlying molecular deficits. To accomplish these goals we propose 3 Projects and 2 Cores: Project 1: Repeat-Associated Non-ATG Translation in DM1 and DM2 Project 2: Mechanisms of RNA-Mediated CNS Pathogenesis in Myotonic Dystrophy Project 3: Clinical and Genetic Characterization of Myotonic Dystrophy Core A: Neuropathology/Functional Imaging Core Core B: Administrative Core.