TITLE: Fibrillin 1 Mutant Mice (W1572C Mutant strain) and (D1545E Mutant Strain)
CASE NUMBER: C13499
ABSTRACT
Fibrillin1 D1545E Mutant Strain
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.
Fibrillin1 W1572C Mutant Strain
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.
FEATURES
These mouse strains are direct correlates of a human disease called stiff skin syndrome. One line has a knock-in missense mutation previously observed in human patients, while the other has a mutation that specifically perturbs integrin binding to fibrillin-1. To our knowledge, these are the first genetic murine models of highly penetrance and spontaneous tissue fibrosis that directly recapitulate both the mechanism and phenotype of a defined human disease.
DESCRIPTION DETAILS
Fibrillin1 D1545E Mutant Strain (Jackson Laboratory Stock No: 025473)
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)
Development
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. ©The Jackson Laboratory 2016 used with permission.
Fibrillin1 W1572C Mutant Strain (Jackson Laboratory Stock No: 025474)
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.
Development
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. ©The Jackson Laboratory 2016 used with permission.
INVENTORS: Harry Dietz, Elizabeth Gerber
ASSOCIATED PUBLICATIONS: Nature. 2013 Nov 7;503(7474):126-30.
CONTACT INFORMATION
Nakisha Holder
Licensing Associate
Johns Hopkins Technology Ventures
410-516-7787
nickki@jhu.edu
