DUX4 and Facioscapulohumeral Muscular Dystrophy

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DESCRIPTION (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) is the third most common genetic disease of skeletal muscle, affecting approximately 1 in 20,000 persons. In contrast to most other muscular dystrophies, the molecular mechanisms responsible for FSHD remain unknown. More than 95% of cases of FSHD are associated with a partial deletion in an array of tandemly repeated 3.3 kilobase DNA units (D4Z4 repeat) near the telomeric region of chromosome 4q35; however, a specific genetic abnormality that causes the disease has not been identified. We have characterized a gene called DUX4 within each of the repeat elements at the FSHD locus and have obtained preliminary evidence that the encoded protein is expressed in muscle from affected subjects. The DUX4 protein appears to be localized to the nuclear envelope, the same location as emerin and lamins A and C, which are mutated in Emery-Dreifuss muscular dystrophy. This Exploratory/Developmental [R21] proposal is designed to further evaluate the expression of DUX4 in FSHD and to obtain pilot data on its function. Aim 1 will assess the expression of DUX4 in cells from patients with FSHD. Expression of the protein will be assessed by immuoblotting, immunofluorescence microscopy and mass spectroscopy using myoblasts from patients with FSHD and non-affected controls. In Aim 2, the targeting of the DUX4 protein to the nuclear envelope and its distribution throughout the cell cycle will be examined. Searches for DUX4 binding proteins, including the nuclear envelope proteins lamins and emerin, will be performed. Potential binding of DUX4 will also be investigated. As programmed cell death occurs in FSHD, the ability of DUX4 to induce apotosis will also be evaluated. The results obtained for DUX4 will be compared to DUX1, a non-pathological paralogue expressed in normal muscle cells. The results of this Exploratory/Developmental [R21] project will establish if abnormal expression of DUX4 occurs in FSHD and provide the prerequisite pilot data and direction for future studies on its role in disease pathogenesis. This work could lead to the development of new diagnostic methods as well as the identification of potential protein targets for the treatment of FSHD.