These mice carry a D1545E mutation in the mouse Fbn1 gene and serve as a model of human stiff skin syndrome with increased collagen deposition in the dermis, decreased subcutaneous fat, and circulating anti-nuclear and anti-topoisomerase I antibodies.
Harry Dietz, Johns Hopkins Medical Institute
Stiff skin syndrome (SSS), a form of scleroderma defined by a pathological fibrosis of the skin, is caused by heterozygous missense mutations in the Arg-Gly-Asp (RGD) integrin-binding domain of the FBN1 (fibrillin 1) gene.
These mice carry a D1545E (RGD to RGE) mutation in the mouse Fbn1 gene that is predicted to cause an obligate loss of integrin binding to fibrillin 1. The mutation is widely expressed in tissues including the skin, aorta, lungs and liver. Heterozygotes serve as a model of human stiff skin syndrome with increased collagen deposition in the dermis by 1 month of age, decreased subcutaneous fat by 3 months of age, disorganized and excessive microfibrillar aggregates in the dermis, and circulating anti-nuclear and anti-topoisomerase I antibodies by three months of age. Mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells, and plasma cells. Homozygosity for the D1545E mutation causes embryonic lethality before embryonic day 10.5 (E10.5)
Site-directed mutagenesis was used to create a D1545E mutation in exon 38 of the targeted gene. A loxP-flanked neomycin resistance cassette was placed upstream in intron 37. The targeting vector was electroporated into (129X1/SvJ x 129S1/Sv)F1- Kitl+-derived R1 embryonic stem (ES) cells and the resultant chimeric mice were bred to C57BL/6J animals. The floxed neomycin cassette was excised through crosses with an EIIa-Cre strain (see Stock No. 003724). This strain was backcrossed to C57BL/6J for 4 generations by the donating laboratory (see SNP note below).
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. 12 of the 17 markers across the genome, as well as 5 markers that distinguish C57BL/6 substrain, were segregating, suggesting an incomplete backcross.
|Allele Name||targeted mutation 2.1, Harry C Dietz|
|Allele Type||Targeted (Not Applicable)|
|Gene Symbol and Name||Fbn1, fibrillin 1|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl+|
|Molecular Note||Exon 38 was replaced with a floxed neomycin resistance cassette and a modified exon 38 in which nucleotide substitutions result in the amino acid substitution of glutamic acid for aspartic acid at position 1545 (D1545E). This mutation destroys the integrin binding site. Cre-mediated recombination removed the selection cassette.|
Heterozygotes are viable and fertile. Homozygotes die before embryonic day 12.5 (E12.5).
When using the Fbn1 D1545E mouse strain in a publication, please cite the originating article(s) and include JAX stock #025473 in your Materials and Methods section.