Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD), which is an autosomal dominant inheritance multisystem disease, is rare, occurring in adulthood, progressive progression, and often results in the death of patients. Clinically, IBMPFD is characterized by limb-girdle muscle dystrophy syndrome sighted proximal and distal muscle weakness, early-onset bone Paget’s disease, and premature frontotemporal dementia. First, in 2004, the IBMPFD disease locus was mapped at the p21-p12 locus of chromosome 9 and was associated with mutations observed in the p97/VCP gene. Biologically, p97/VCP has been shown to have a regulatory and catalyzing role in many cellular processes, including postmitotic homotypic membrane fusion, nuclear sheath regeneration and packaging, cell cycle regulation, programed cell death, endoplasmic reticulum-associated degradation, organelle biogenesis, regulation of transcription factors, Endoplasmic reticulum membrane fusion, stimulation of B and T cells, and inhibition and separation of protein aggregates. IBMPFD has been associated with mutations observed in the p97/VCP gene. Currently, the number of p97/VCP mutations identified in IBMPFD patients is 28. The molecular mechanisms of only a few of these mutations in IBMPFD pathogenesis were understood. In this review, all of the p97/VCP mutations associated with IBMPFD are discussed, and the molecular mechanisms of p97/VCP in disease process are examined.

Keywords: p97/VCP, inclusion body myopathy with early-onset Paget disease and frontotemporal dementia, endoplasmic reticulumassociated degradation