The VapbP56S knock-in allele has the P56S mutation associated with human amyotrophic lateral sclerosis 8 (ALS8) inserted into exon 2 of the vesicle-associated membrane protein-associated protein B and C locus (Vapb).
Homozygous mice (VapbP56S/P56S) exhibit a slowly progressive motor neuron disease with cellular pathological features prior to late-onset motor behavior defects; characteristic of the human ALS8 / spinal muscular atrophy (SMA) associated with VAPBP56S. Specifically, the homozygous cellular pathology is accumulation of VAPBP56S and ubiquitinated proteins in cytoplasmic inclusions (selectively in motor neurons), as well as induction of ER stress and autophagic response in motor neurons.
Heterozygous mice (VapbP56S/+) are less severe; showing mild age-dependent defects in motor behaviors as characteristic features of the disease.
Both heterozygous and homozygous mice are viable and fertile, with normal Mendelian distribution.
The VapbP56S knock-in allele is transcribed at comparable levels to those of the endogenous Vapb gene, but the P56S mutation renders the VAPBP56S protein detergent-insoluble.
The VapbP56S knock-in mice were first published/characterized on the 129SvEv genetic background in 2015, and this phenotype is described above. It should be noted that the phenotype of the C57BL/6-congenic VapbP56S knock-in mice could vary from that originally described on a 129SvEv genetic background. However, the donating investigator reports that VapbP56S knock-in mice on the C57BL/6 background and VapbP56S knock-in mice on the 129SvEv background show the same cellular biological defects; including VAPB positive inclusion and accumulation of ubiquitinated proteins.
