Genetic basis of myopathy with Paget disease of bone

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DESCRIPTION (provided by applicant): Hereditary inclusion body myopathies (h-IBM) are a genetically diverse group of disease characterized by distal/proximal limb-girdle muscle weakness and the presence of inclusion bodies in muscle. We recently identified a new member of this group of disorders [1,2; attached], in which the inclusion body myopathy is associated with Pagets disease of the bone (PDB) and/or frontotemporal dementia (FTD). This new disorder previously diagnosed as a variety of disorders such as limb girdle muscular dystrophy and amyotropic lateral sclerosis has been categorized as IBMPFD (MIM 605382). The inclusion body myopathy is progressive with onset typically in the 30s-40s and associated with early demise. We have identified the gene VCP (Valosin Containing Protein) as being mutated in IBMPFD. The aims of the proposed research project are: 1. Clinical and Molecular studies in families with myopathy associated with Paget disease of the bone (IBMPFD): Recruit new IBMPFD families for clinical evaluations, biochemical, radiological and molecular (DNA) testing. To collect post mortem and biopsy tissue from IBMPFD families for histological and biochemical studies. 2. Screening of VCP in familial HIBM and PDB: 3. Facilitate sharing of results of VCP mutation analysis in a genetic counseling setting with participating research subjects. 4. Development of a Mouse model of IBMPFD: To develop two transgenic mouse lines; one over expressing the common VCP mutation (R155H) and one over expressing wt VCP and study any phenotypic changes at the clinical and molecular level. 5. To characterize VCP pathways and interacting proteins: Basic in vitro studies to characterize the nature of mutations identified in VCP (i.e. effect on ATPase activity, protein-protein interactions, and hexamer formation). Study the VCP specific pathways in C2C12 cell lines (stably transfected wt and R155H VCP) during differentiation and under stress conditions.