Valosin-containing protein (VCP), also known as p97, is an ATPase with diverse cellular functions, including protein quality control, membrane fusion, chromatin remodeling, disassembly of the DNA helicase complex, DNA repair, formation of the endoplasmic reticulum and nuclear envelope, and regulation of RNA stability. Mutations in the human VCP gene are the cause of inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), a degenerative multisystem proteinopathy that causes pathology of the skeletal muscle, brain, bone, and heart. VCPK524A transgenic mice overexpress a K524A (lysine to alanine) point mutant form of mouse Vcp cDNA from the mouse cardiac-specific Myh6 (myosin, heavy polypeptide 6, cardiac muscle, alpha) and tetO promoters. Mutation of lysine 524 to alanine within the D2 ATPase domain results in dramatically reduced ATPase activity and produces a dominant-negative mutation that is deficient in segregase and protein complex remodeling functions. Hemizygotes are viable and fertile. The viability/fertility of homozygotes has not been assessed to date (September 2019). When crossed with Myh6-tTA (<a href="http://www.informatics.jax.org/allele/MGI:3757936">Tg(Myh6-tTA)55Rbns)</a> mice, double transgenic (DTgVCPK242A) hemizygous mutant progeny (untreated with tetracycline/doxycycline) develop dilated cardiomyopathy at 9 months of age. The mice also demonstrate accelerated cardiomyopathy in response to pressure overload. Cardiomyocyte nuclear morphology is profoundly defective, with increased nuclear envelope proteins and nuclear lamins.

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VCPK524A transgenic mice overexpress a K524A (lysine to alanine) point mutant form of mouse Vcp (valosin containing protein) cDNA from the mouse cardiac-specific Myh6 (myosin, heavy polypeptide 6, cardiac muscle, alpha) and tetO promoters. Upon crosses with a tTA-expressing mouse strain, progeny express a VCP protein with dramatically reduced ATPase activity.

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