Presenilin 1 is the catalytic subunit of the gamma-secretase complex which cleaves beta-amyloid precursor protein and NOTCH receptor proteins. These mice carry the c.548G>T
mutation which has been identified in familial frontotemporal dementia patients. Mice that are homozygous for the targeted mutation are viable and fertile. The point mutation was confirmed by sequencing.
Reduced levels and aberrant mRNA is detected by qRT-PCR, RT-PCR and Northern blot analysis of brain tissue from homozygotes. An approximately 30% reduction in PSEN1 protein levels in brains from 2 month old homozygotes is detected by Western blot analysis.
Aberrant mRNA are not detected and mRNA levels are unaltered in liver, lung, skin and splenocytes. γ-secretase activity is decreased in the cerebral cortex of homozygotes.
A targeting vector was designed (by site-directed mutagenesis) to introduce a c.548G>T mutation in the last nucleotide of exon 6 of the Psen1 gene, causing a single amino acid substitution of valine for glycine at position 183 (G183V). This mutation has been identified in human familial frontotemporal dementia patients. The construct, which also contained a floxed PGK-neo cassette, was electroporated into (C57BL/6 x 129)F1 derived MKV6.5 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting male chimeric
mice were mated with C57BL/6J-129 F1 females. The females carrying the allele were bred to α CaMKII-Cre male transgenic mice (carrying the (Tg(Camk2a-cre)1Shn transgene and on the C57BL/6J background) to excise the floxed PGK-neo selection cassette. The mice were the backcrossed to C57BL/6 for 13 generations.
Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.
|Allele Name||targeted mutation 3.1, Jie Shen|
|Allele Type||Targeted (Humanized sequence)|
|Gene Symbol and Name||Psen1, presenilin 1|
|Strain of Origin||(C57BL/6 x 129)F1|
|Molecular Note||Exon 6 was replaced with a floxed neo cassette and a modified exon 6 with a transversion (c.548G>T) that results in the amino acid substitution of valine for glycine at position 183 (G183V), mimicking a mutation found in family suffering from a frontotemporal dementia (FTD). Cre-mediated recombination removed the neo cassette.|
When maintaining a live colony, these mice can be bred as homozygotes.
When using the c.548GTKI mouse strain in a publication, please cite the originating article(s) and include JAX stock #027082 in your Materials and Methods section.