Hereditary inclusion body myopathy (h-IBM), Paget disease of bone (PDB) and/or frontotemporal dementia (FTD), also called IBMPFD was recognized as a distinct clinical syndrome in 2000 by Kimonis et al. who identified that the disease is caused by mutations in the Valosin Containing Protein (VCP) gene. Over 30 families from North and South America, Europe and Australia harboring 15 unique VCP missense mutations have been recruited for our gene discovery studies. We now propose to perform detailed clinical studies in 50 affected and 25 unaffected individuals to determine the rate of progression of the disease so that the effects of future treatment strategies can be objectively evaluated. We have created a knock-in mouse model that demonstrates decreased muscle strength, disrupted muscle fibers, TDP-43 and ubiquitin positive inclusion bodies and vacuoles in muscle, cognitive deficits and Paget-like bone lesions. Additionally, we have identified a number of molecular and cellular defects in patients'muscle cells and tissues.
The aims of the proposed project are: 1. Clinical studies in patients with myopathy associated with Paget disease of the bone (IBMPFD) to evaluate disease progression 2. To characterize the phenotype and tissue pathology of the R155H knock-in mouse model of IBMPFD 3. To characterize the molecular pathogenesis of muscle from patients and mice at different stages of the myopathy 4. To clarify the cellular pathology of mutant primary myoblasts from patients Insight into the disease pathogenesis gained by our detailed clinical evaluations, analysis of muscle tissue from patients and mice and patient myoblasts will provide hypotheses that can be tested by parallel studies of patients and knock-in VCP mice.
We have established hereditary inclusion body myopathy (h-IBM), Paget disease of the bone (PDB) and frontotemporal dementia (FTD), called IBMPFD (MIM 167320) as a significant disorder associated with mutations in the VCP (Valosin Containing Protein) gene. It is a progressive condition with onset typically between the 20s to 30s. The main features of VCP limb girdle myopathy are weakness and atrophy of the skeletal muscles of the pelvis and shoulder, and the presence of rimmed vacuoles and inclusion bodies in the muscle fibers. PDB due to excessive activity of bone osteoclast cells causes pain of affected bones typically of the pelvis, spine and scapula and increased predisposition to fractures and malignancy. FTD is often associated with a lack of inhibition, as well as with impulsive or inappropriate behavior. Affected individuals die from progressive muscle weakness, as well as from cardiac and respiratory failure typically in their 40s to 50s. Our preliminary studies reveals that our knock-in mice have many features of the human disease and will prove to be an excellent model to study. Results from these proposed comprehensive studies in patients, their muscle samples, gene expression profiles, myoblasts, and our knock-in mouse model will clarify the molecular mechanisms for disease progression. These studies will permit cooperative studies simultaneously in humans and mice which we hope will lead to a cure for this disease.
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