Molecular mechanism of FSHD pathology

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DESCRIPTION (provided by applicant): Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant myopathy characterized by progressive weakening of the facial, shoulder, and upper arm muscles. FSHD is not caused by a mutation in a protein-encoding gene; instead the genetic lesion in >98% of cases is a contraction in the number of non-coding D4Z4 DMA repeats specifically on chromosome 4q35. How this genome deletion leads to pathology is not understood, however, strong evidence indicates that genes localized proximal to the 4q35 deletion are mis-expressed in FSHD affected skeletal muscles. One such gene is FRG1 (FSHD region gene 1) the first transcribed gene identified that localized to 4q35 and the best overall candidate for mediating the pathology of FSHD. The FRG1 gene is conserved from C. elegans to humans, but still very little is known about the function of the FRG1 protein (FRG1P) in any system. This proposal directly addresses the nuclear function of FRG1P and the effects of misregulation of FRG1P expression levels in a novel vertebrate model for FSHD. The system for these studies is the vertebrate developmental model organism, Xenopus laevis (African clawed frog). Xenopus, with its external development and the ease of generating large numbers of transgenic animals, is ideal among available model systems for investigating FRGIP's role in FSHD pathogenesis. In Aim 1 the transgenic FSHD-like animals will be further characterized for an FSHD pehntype in regards to muscle structure, physical characteristics, and behavior. Aim 2 directly address function of FRG1P by using transgenic frogs to alter the expression levels of FRG1P domains during development, identifying the molecular mechanism of FSHD pathology. Proteins and nucleic acids that interact with FRG1P will be identified in Aim3. Ultimately, the goal of FSHD research is to find treatments. The epigenetic mis-regulation in FSHD will be extremely difficult to adress. The best viable targets for therapy are the affected gene (FRG1) or its downstream targets. An extension of Aim 1 proposes to test the FSHD-like frogs for thier ability to have the FSHD phenotype reversed or at leased lessened by reducing or eliminating FRG1 over-expression. Success of this line of experiments will indicate the feasibility of a small molecule screen for FSHD treatments. Xenopus FSHD-tadpoles develop externally and are transparent rendering them ideal for testing small molecule therapeutics to find a cure for FSHD.