These knockin mice carry an amino acid substitution, R76H in exon 1of the Gfap gene. Mutations in Gfap or glial fibrillary acidic protein, are associated with Alexander disease (AxD), a rare disorder of astrocytes.
Dr. Albee Messing, University of Wisconsin-Madison
Gfap or glial fibrillary acidic protein is a major intermediate filament protein found in mature astrocytes. An amino acid substitution, R79H, found in Gfap is associated with Alexander disease (AxD), a rare disorder of astrocytes. This knockin strain carries the corresponding mutation in the mouse, R76H in exon 1. Homozygous mice are viable and fertile. Both heterozygous and homozygous mice exhibit Rosenthal fibers, the hallmark protein aggregates found in astrocytes from the hippocampus, corpus callosum, olfactory bulbs and periventricular regions. Other similarities include an increase in antioxidant response element (ARE) activation and in both soluble and insoluble GFAP, however, the mouse pathology more closely resembles adult AxD rather than the more severe infantile AxD. This strain may be useful for studying Alexander disease.
The targeting vector was designed (by site-directed mutagenesis) to insert the arginine to histidine amino acid substitution at position 76 (R76H) (human 79) into exon 1 and place a loxP-flanked neomycin cassette into intron 3.
The construct was electroporated into 129S7/SvEvBrd-derived AB1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were crossed to 129S6/SvEvTac. Offspring were then crossed to mice expressing a nervous system specific Cre recombinase (nestin-cre) on an unspecified genetic background, to remove the neomycin cassette. These mice were then crossed to FVB/NJ for at least 20 generations. Upon arrival at The Jackson Laboratory, the mice were crossed to FVB/NJ at least once to establish the colony.
|Allele Name||targeted mutation 3, Albee Messing|
|Allele Type||Targeted (Humanized sequence)|
|Allele Synonym(s)||GFAP R76H; Gfaptm1Hgmn|
|Gene Symbol and Name||Gfap, glial fibrillary acidic protein|
|Strain of Origin||129S7/SvEvBrd-Hprt+|
|Molecular Note||The targeting vector was designed (by site-directed mutagenesis) to insert the arginine to histidine amino acid substitution at position 76 (R76H) (human 79) into exon 1 and place a loxP-flanked neomycin cassette into intron 3. R79H is associated with Alexander disease in humans. Cre-mediated recombination removed the floxed neo cassette. Quantitative real-time PCR showed that Gfap expression is elevated.|
While maintaining a live colony, these mice are bred as heterozygotes. Homozygotes do not breed well.
When using the GFAP R76H mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #37136 in your Materials and Methods section.