A TANDEM DUPLICATION WITHIN THE FIBRILLIN-1 GENE IS ASSOCIATED WITH THE MOUSE TIGHT-SKIN MUTATION

Mice carrying the Tight skin (Tsk) mutation have thickened skin and vi sceral 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 myocardi al hypertrophy. Previously we localized Tsk to mouse chromosome 2 in a region syntenic with human chromosome 15. The microfibrillar glycopro tein gene, fibrillin I (FBN1), on human chromosome 15q, provided a can didate for the Tsk mutation. We now demonstrate that the Tsk chromosom e harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame Fbn1 transcript. These Findi ngs provide hypotheses to explain some of the phenotypic characteristi cs of Tskl + mice and the lethality of Tsk/Tsk embryos.