Scleroderma or systemic sclerosis (SSc) is a rare human disease of unknown etiology (but believed to have an autoimmune basis) in which both genetic and environmental contributions have been proposed. In Caucasian populations, the prevalence of SSc is low (2.1 - 25.3 cases per 100,000), and familial aggregation is quite uncommon. Because of this the identification of genetic risk factors has been extremely difficult. Recently, we have identified an inbred human population in which SSc occurs frequently. Full-blooded Choctaw Native Americans living in southeastern Oklahoma have the highest prevalence of SSc yet found (469 cases per 100,000). There was a striking genetic association of the disease with a uniquely Amerindian HLA haplotype (HLA-DRB1*1602) which conferred a relative risk for SSc of 21. In another group of full-blooded Choctaws living in Mississippi in whom this same HLA haplotype is common, we were unable to identify any cases of SSc. Since Oklahoma Choctaw migrated from Mississippi in the early 1800's, non-HLA founder genes for SSc may have been introduced into ancestors of the Oklahoma Choctaws. Furthermore, genealogic tracing of contemporary Oklahoma Choctaw SSc cases unequivocally linked 20/25 cases to five founding families in the late 1700's, suggesting that such a """"""""""""""""founder effect"""""""""""""""" indeed may have occurred. A novel rearrangement in the fibrillin-1(Fbn1) was recently reported in the tight skin 1 mouse (Tsk1), a model of human SSc. This provided a rational candidate on human chromosome 15q (homologous to the Tsk1 locus) to search for these susceptibility in this relatively isolated population using linkage disequilibrium between microsatellite alleles and the disease promoting genes. Microsatellite alleles near the FBN1 gene, including two intragenic markers, were significantly increased in the SSc cases vs. controls. Family studies established that these microsatellite alleles constituted a 2-7 cM haplotype that was more significantly increased in cases vs. controls (7/18 vs. 6/77, p=0.0024). Probability calculations demonstrated that the likelihood of this haplotype sharing occurring by chance is very low (p=1.7x10-15), implicating FBN1 as a likely candidate gene for human SSc. Thus, the overall aims of this proposal are to undertake a detailed study of fibrillin-1 in SSc.
Our specific aims are as follows: 1. To examine cellular processing of fibrillin-1 in the fibroblasts from SSc patients using standard pulse-chase methods. 2. To characterize the ultrastructural features of fibrillin-1 in SSc fibroblasts 3. To screen the entire FBN1 gene for mutations or polymorphisms associated with SSc 4. To determine if fibrillin-1 abnormalities occur in all or only specific clinical or autoantibody subsets of SSc or only in certain ethnic groups.

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