B6;129S-Vcp^tm1Itl/J

Stock number: 021968
Research areas: Endocrine Deficiency Research, Internal/Organ Research, Neurobiology Research

Description

These Vcp^R155 mice contain a mutation of the valosin containing protein (Vcp) gene, commonly found in patients with Inclusion Body Myopathy with Early-Onset Paget Disease and Frontotemporal Dementia (IBMPFD).

Detailed description

These mice contain the R155H mutation of the valosin containing protein (Vcp) gene, commonly found in patients with Inclusion Body Myopathy with Early-Onset Paget Disease and Frontotemporal Dementia (IBMPFD). IBMPFD is characterized by progressive muscle weakness, bone deformities and extensive neuro-degeneration resulting in respiratory and cardiac failure. Heterozygotes are viable and fertile, while homozygotes do not breed. Heterozygous mice exhibit progressive muscle weakness starting at six months of age, with progressive vacuolization of myofibrils and centrally located nuclei within the muscle. The quadriceps myofibrils and brain contain cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies. Muscle fibers show central nucleation and altered sarcomere ultrastructure, as well as increased autophagy and apoptosis. Bone marrow derived macrophages from these mice display an increased rate of osteoclastogenesis. Distal femurs and proximal tibiae show decreased trabecular connectivity density, increased cortical wall thickness, and decreased bone density. 15% of heterozygous mice exhibit seizures.

Development

A targeting vector was designed to introduce the R155H mutation of the valosin containing protein gene (Vcp), commonly found in patients with Inclusion Body Myopathy with Early-Onset Paget Disease and Frontotemporal Dementia (IBMPFD). The targeting vector also contained a frt-flanked neo cassette downstream of exon 5. This construct was electroporated into 129/SvEv-derived embryonic stem (ES) cell line. Correctly targeted ES cells were injected into 129/SvEv blastocysts and the resulting chimeric males were bred to 129/SvEv females. The donating investigator reported that these Vcp^R155H mice were backcrossed to C57BL/6JEiJ mice for at least six generations prior to sending to The Jackson Laboratory Repository in 2013 (see SNP note below). Upon arrival, sperm was cryopreserved. To generate our living colony, an aliquot of the frozen sperm was used to fertilize oocytes from C57BL/6JEiJ female mice (Stock No. 000924).

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. Four markers throughout the genome suggested an in complete backcross.

Allele

Symbol: Vcp^tm1Itl
Name: targeted mutation 1, inGenious Targeting Laboratory
MGI accession ID: MGI:4849540
Generation method: Targeted
Marker symbol: Vcp
Marker name: valosin containing protein
Chromosome: 4
Strain of origin: 129S6/SvEvTac
Molecular note: Nucleotide substitution results in the amino acid substitution of histidine for arginine at position 155 (R155H). A floxed and FRT-flanked neo cassette was inserted downstream of exon 5.