Induction of skin fibrosis in mice expressing a mutated fibrillin-1 gene.
BACKGROUND
Tight skin mice (TSK) bear a mutated Fibrillin-1 (Fbn-1) gene. Genetic studies show that the TSK mutation is closely associated with the Fbn-1 locus (0-0.7 cM). A previous study showed two recombinants between the Fbn-1 locus and the TSK mutation. TSK mutation and mutated Fbn-1 gene cosegregate in F1 mice.


METHODS
To elucidate the role of the mutated Fbn-1 gene in occurrence of TSK syndrome, we generated transgenic (Tg) mice expressing mutated Fbn-1 gene. In another set of experiments, we injected normal mice after birth with a plasmid bearing mutated Fbn-1 gene (pdFbn-1).


RESULTS
Our results demonstrate that the pdFbn-1 Tg mice developed permanent cutaneous hyperplasia that was permanent. In mice injected as newborns with a plasmid bearing the sense pdFbn-1 gene, cutaneous hyperplasia was transient. In contrast to TSK mice, neither Tg nor mice injected with plasmid developed lung emphysema. The pdFbn-1 Tg and TSK mice spontaneously produced anti-topoisomerase I and anti-Fbn- antibodies, as do humans afflicted by scleroderma; whereas, those injected with a plasmid containing the pdFbn-1 gene produced only anti-Fbn-1 autoantibodies.


CONCLUSIONS
The results suggest that, although cutaneous hyperplasia is due to mutated Fbn-1 gene, the TSK syndrome may be multifactorial.
Saito
S
S
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Nishimura
H
H
Phelps
R G
RG
Wolf
I
I
Suzuki
M
M
Honjo
T
T
Bona
C
C
D000818:Animals; D000071838:Fibrillin-1; D000071837:Fibrillins; D005355:Fibrosis / Q000235:genetics*; D005838:Genotype; D006909:Hydroxyproline / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D010957:Plasmids; D012867:Skin / Q000473:pathology*; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D006909:Hydroxyproline; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse