Drosophila as a model for Emery-Dreifuss muscular dystrophy

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DESCRIPTION (provided by applicant): Lamins form a meshwork that lines the inner nuclear envelope, providing structural support for the nucleus and organizing the genome through contacts made with chromatin. Lamins participate in diverse nuclear processes such as the regulation of gene expression, DNA replication/repair and signal transduction. In humans, mutations in the LMNA gene, encoding the A-type lamins, cause a collection of diseases known as laminopathies, including autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) and dilated cardiomyopathy. Though lamins are expressed in nearly all cells, defects occur in specific tissues. For example, muscle tissue is especially sensitive to mutant forms of A-type lamin. We developed a powerful Drosophila model for studying the function of A-type lamins. Mutant forms of the Drosophila A-type lamin analogous to those that cause disease in humans have been expressed in transgenic flies. When these mutant forms are expressed in larval muscle, muscle defects arise that result in semi-lethality. Adult "escapers" possess leg defects consistent with a loss of larval muscle function. In Specific Aim 1 we will perform a whole organism drug screen to identify compounds that rescue the mutant phenotypes and/or lethality associated with expressing mutant forms of lamin in muscle. This screen will be carried out in collaboration with Ross Cagan (Mt. Sinai School of Medicine), an expert in Drosophila drug screens. In Specific Aim 2 we will test the function of A-type lamin variants that have been identified in patients by Drs. Katherine Matthews, Steven Moore and Peter Nagy (University of Iowa). We will functionally test these variants by expressing them in Drosophila muscle and assaying for molecular defects and loss of muscle function. Collectively, our studies link clinical investigations with basic lamin research and have the potential to identify new compounds for the treatment of AD-EDMD. PUBLIC HEALTH RELEVANCE: Emery-Dreifuss muscular dystrophy (EDMD), a rare form of muscular dystrophy that causes progressive muscle wasting and cardiac failure, is estimated to occur in 1-2/100,000 individuals. EDMD is one of twelve diseases classified as "laminopathies", which are caused by mutations in the gene encoding lamin, a component of the nuclear envelope. We have assembled a team of basic researchers and clinicians that share the goal of identifying a therapy for EDMD. To reach this goal we will use a fruit fly model of EDMD. This invertebrate model allows for whole organism drug screens. Our studies will provide functional tests for lamins and identify compounds for possible therapeutic treatment of EDMD.