The Tight Skin (Tsk) Mutation in the Mouse, a Model for Human Fibrotic Diseases, Is Tightly Linked to the β2-Microglobulin (B2m) Gene on Chromosome 2

Siracusa, Linda D.; Christner, Paul J.; McGrath, Rodney; Mowers, Sheryl D.; Nelson, Kelly; Jimenez, Sergio A.

doi:10.1006/geno.1993.1398

Cited by 26 publications

(12 citation statements)

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“…The surviving animals developed severe dermal fibrosis, which displayed remarkable similarities to the histopathologic skin changes characteristic of human SSc. Our group of investigators has described 2 other mutant murine models of SSc which clearly mimic the fibrotic aspects of the human disease but do not display many of the classic symptoms of GVHD (28)(29)(30)(31)(32). In early chronic murine GVHD, mononuclear cells localized deep within the dermis are associated with fibroblasts displaying increased collagen production (33).…”

Section: Conclusion the Results Suggest That Vinyl Chloride Injectiomentioning

confidence: 99%

Increased numbers of microchimeric cells of fetal origin are associated with dermal fibrosis in mice following injection of vinyl chloride

Christner

Artlett

Conway

et al. 2000

Arthritis & Rheumatism

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Objective. To develop a murine model for use in examining the role of microchimeric cells and certain chemical exposures in the pathogenesis of systemic sclerosis (SSc). Methods. Female BALB/cJ retired breeder mice were bled before and after vinyl chloride injection. The DNA from their white blood cells was obtained, and the number of microchimeric cell equivalents was determined by quantitative polymerase chain reaction using DNA primers specific for the H-2K b gene, a sequence not found in BALB/cJ mice. Skin was obtained at autopsy, embedded in paraffin, sectioned, and stained with Masson's trichrome. Hydroxyproline analyses were performed on 4-mm skin biopsy samples. Results. Microchimeric cells were identified and quantitated before and after 20 daily intraperitoneal injections of vinyl chloride. The number of microchi-meric cells in the peripheral blood increased an average of 48-fold after treatment with vinyl chloride. Histologic examination of the skin of these same mice (which had an increased number of microchimeric cells) showed inflammation, with abundant fibroblasts and a heavy mononuclear infiltration in the dermis. The collagen fibers appeared densely packed and disorganized. His-tologic examination of the skin of untreated retired breeder mice and treated virgin mice appeared normal. Quantitative assays to determine the collagen content of skin biopsy samples obtained from treated microchi-meric mice compared with nontreated microchimeric or with treated nonmicrochimeric mice showed a 2-3-fold increase in collagen content in the treated microchi-meric mice. Extraordinary splenomegaly was present in the vinyl chloride-treated microchimeric mice, accompanied by cellular infiltration and fibrosis. Conclusion. The results suggest that vinyl chloride injections into BALB/cJ retired breeder mice lead to activation of microchimeric cells, which causes the cells to divide and multiply. The correlation between the 48-fold increase in microchimeric cells and the appearance of dermal inflammation and fibrosis similar to that of graft-versus-host disease suggests that activated mi-crochimeric cells may be a necessary factor in the pathogenesis of autoimmune diseases such as SSc.

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Section: Conclusion the Results Suggest That Vinyl Chloride Injectiomentioning

confidence: 99%

Increased numbers of microchimeric cells of fetal origin are associated with dermal fibrosis in mice following injection of vinyl chloride

Christner

Artlett

Conway

et al. 2000

Arthritis & Rheumatism

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“…1) and mapped Fbnl in an intersubspecific backcross involving Mus castaneus (CAST) and C57BE/6 (B6) pa +/+ Tsk mice (see Methods). Genomic DNA from N 2 progeny carrying Tsk was subjected to Southern blot and PCR analyses to identify restriction fragment and simple sequence length polymorphisms (Siracusa et al 1993). A 494-bp mouse Fbnl cDNA probe (3' UTR) from the 3'-untranslated region (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mice carrying Tsk and pa were maintained at the Jefferson Medical College (Philadelphia, PA). The intersubspecific backcross of [CAST x (CAST • B6 pa +/+ Tsk)F1] mice was as described (Siracusa et al 1993). Only N 2 progeny displaying the mutant Tsk phenotype, as determined by manual assessment of the thickness and tightness of the skin in the interscapular region, were used.…”

Section: Micementioning

confidence: 99%

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A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation.

Siracusa¹,

McGrath²,

Ma³

et al. 1996

Genome Res.

277

204

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Mice carrying the Tight skin (Tsk) mutation have thickened skin and visceral fibrosis resulting from an accumulation of extracellular matrix molecules. These and other connective tissue abnormalities have made Tskl + mice models for scleroderma, hereditary emphysema, and myocardial hypertrophy. Previously we localized Tsk to mouse chromosome 2 in a region syntenic with human chromosome 15. The microfibrillar glycoprotein gene, fibrillin 1 (FBN1), on human chromosome 15q, provided a candidate for the Tsk mutation. We now demonstrate that the Tsk chromosome harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame Fbn1 transcript. These findings provide hypotheses to explain some of the phenotypic characteristics of Tskl + mice and the lethality of Tsk/Tsk embryos.

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“…Initially mapped to mouse chromosome 2 in the region of the pallid locus [2], subsequent genetic analyses refined the genetic map [5] leading to the identification of the Tsk mutation as a large in frame intragenic duplication of the fibrillin 1 gene (Fbn1) [6]. Molecular studies have demonstrated the presence of a normal 11 kb Fbn1 transcript and a mutant 14 kb transcript in RNA extracts prepared from Tsk/+ mice [6].…”

Section: Tight Skinmentioning

confidence: 99%

Animal models in scleroderma

Clark

2005

Curr Rheumatol Rep

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Scleroderma or systemic sclerosis is an insidious connective tissue disease with no known cure. A hallmark feature of scleroderma is the excess synthesis and deposition of collagen resulting in a fibrotic state. In scleroderma, fibrosis is not confined only to the skin but impacts internal organs as well. In an effort to better understand the pathophysiology of this disease, researchers have developed a variety of animal models that display features of the human condition. This paper focuses on mouse models of scleroderma and summarizes work conducted with these experimental paradigms that is focused on understanding the cellular and molecular events associated with the onset and maintenance of fibrosis.

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The Tight Skin (Tsk) Mutation in the Mouse, a Model for Human Fibrotic Diseases, Is Tightly Linked to the β2-Microglobulin (B2m) Gene on Chromosome 2

Cited by 26 publications

References 0 publications

Increased numbers of microchimeric cells of fetal origin are associated with dermal fibrosis in mice following injection of vinyl chloride

Increased numbers of microchimeric cells of fetal origin are associated with dermal fibrosis in mice following injection of vinyl chloride

A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation.

Animal models in scleroderma

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