Posted 7 December 2010

General Information

Human VCP (Valosin-containing protein) cDNA was obtained from Origene. Disease associated mutations R155H and A232E were introduced using the QuickChange Site-Directed Mutagenesis Kit (Stratagene) as directed. The cDNA was then subcloned into the SmaI site of pCX-A. DNA was microinjected into male SJL pronuclei, which were then transferred to foster females. Positive founders were bred to C57/B6 animals to produce F2 progeny.

Mutation: R155H and A232E.

Promoter: N/A

Mouse strain: SJL. Origin: C57/B6; Background: C57/B6 F2.

Phenotype

Neuropathological analysis:

Recapitulate spectrum of disease in human inclusion body myopathy with Paget’s frontotemporal dementia (IBMPFD). Pathological examination of the brain shows widespread TDP-43 pathology.

Behavioral Phenotype:

The mice exhibit abnormalities in behavioral testing. Progressive muscle weakness. Severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. Wt and mutant mice develop normally initially, but both mutants began to show adult-onset weight loss at ~9 months of age and continued to decline relative to wt. At 3-6 months some mutant mice show hindlimb clasping phenotype increasing in severity over time.

Availability

Contact: J. Paul Taylor
Developmental Neurobiology, MS 343, D-4026, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-, Phone: +90115956047, Fax: +90115952032

References

Primary:

Custer SK, Neumann M, Lu H, Wright AC, Taylor JP. Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone. Hum Mol Genetics 2010, 19(9):1741-1755. Abstract