These mice carry a W1572C 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 W1572C mutation (equivalent of the human W1570C mutation) in the mouse Fbn1 gene. 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. Mice homozygous for the W1572C mutation are viable and show accelerated skin fibrosis when compared with heterozygous littermates.
Site-directed mutagenesis was used to create a W1572C mutation (equivalent of the human W1570C 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. Eight of the 27 markers throughout the genome were segregating, suggested an in complete backcross. Three of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.
|Allele Name||targeted mutation 3.1, Harry C Dietz|
|Allele Type||Targeted (Humanized sequence)|
|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 cysteine for tryptophan at position 1572 (W1572C). This mutation is associated with stiff skin syndrome (SSS) in human patients. Cre-mediated recombination removed the selection cassette.|
Heterozygotes are viable and fertile. Homozygous fertility is reduced slightly in males, more so in females.
When using the Fbn1 W1572C mouse strain in a publication, please cite the originating article(s) and include JAX stock #025474 in your Materials and Methods section.