Functional interactions of the sZM domain that is mutated in zaspopathy were investigated using yeast two-hybrid, immunoprecipitation, co-sedimentation, and slot blot overlay assays. HIS-ZASP and GST-ZASP proteins were used for in vitro functional assays. ZASP-GFP cDNA were expressed in cultured C2C12 cells and in adult mouse tibialis anterior muscle by intramuscular injection. Morphology was examined with immunofluorescence and electron microscopy. We show the following results from our experiments performed during last year: 1) ZASP directly binds to skeletal muscle -actin and the conserved domain that is mutated in myopathy is important for ZASP-actin interaction. 2) Both wild type and mutant ZASP bind to -actin and -actinin, the core structure of Z-discs, but only the mutant protein causes disruption of -actinin-crosslinked actin filaments assembled in vitro, in cultured muscle cells, and in adult mouse skeletal muscle. Focal accumulations of F-actin that co-localize with ZASP are detected in patients skeletal muscle fibers. 3) The deleterious effects of the mutant ZASP are specific to the long ZASP isoform that is expressed in post-natal muscle, therefore suggesting that RNA splicing and the second actin-binding site generated thereof are modulators of the disease process. 4) We propose that mutant ZASP destabilizes the protein assemblies within cytoskeletal scaffolds that are important for maintaining the integrity of -actin lattices at the Z-discs of striated muscle. 5) Our results support dominant gain-of-function disease mechanism in zaspopathy. The above results have been submitted for a publication and is under review. We completed enrollment of subjects (n=33) to the DMD Imaging study (protocol ID 11-N-0261). We have begun the analysis of the data. Clinical observations in one of the research subjects will be published soon (see below). We have identified novel gene defects and known gene mutations in several of our patients including the ones in the Neurogenetics clinic by using NextGen exome analysis. One such research collaboration will result in a publication in near future (collaborators: Drs. Charlotte Sumner, the Johns Hopkins, and Henry Houlden, UK)

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Mankodi, Ami; Grunseich, Christopher (2015) Toe-extension myotonia in myotonic dystrophy type 1. Neurology 85:203
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