Association of 5'-untranslated region of the Fibrillin-1 gene with Japanese scleroderma.

Excessive production of extracellular matrix (ECM) constituents is a hallmark scleroderma or systemic sclerosis (SSc). Fibrillin-1, a major component of microfibrils in the ECM, may play a role in the pathogenesis of SSc. The TSK1 mouse model of SSc bears an in-frame duplication of the Fibrillin-1 gene (FBN1) which results in a larger than normal protein that is more susceptible to proteolysis. Metabolic labeling studies of Fibrillin-1 in human SSc dermal fibroblasts demonstrated that while normal amounts of Fibrillin-1 are synthesized, the protein itself appears to be unstable. Moreover, autoantibodies specific for Fibrillin-1 have been demonstrated in serum from SSc patients and TSK1 mice. In particular, a high frequency of anti-Fibrillin-1 was observed in Japanese patients with diffuse and limited scleroderma or CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome. Genetic studies in a Native American population with high prevalence of using microsatellite marker showed strong association between FBN1 haplotypes and SSc. Subsequently, studies of FBN1 single nucleotide polymorphisms (SNPs) demonstrated that certain FBN1 haplotypes were associated with SSc in both Native American and Japanese patients with limited scleroderma. Thus, FBN1 was sequenced in 22 Japanese SSc patients to ascertain the presence of any relevant mutations or SNPs. Sequence analysis revealed eight coding and 14 non-coding SNPs and other polymorphisms. Among them, a CT insertion in the 5'-untranslated region of exon A had a significant negative association with disease.