Kodera Takao, Tan Filemon K, Sasaki Takeshi, Arnett Frank C, Bona Constantin A
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Gene. 2002 Sep 4;297(1-2):61-7. doi: 10.1016/s0378-1119(02)00862-4.
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.
细胞外基质（ECM）成分的过度产生是硬皮病或系统性硬化症（SSc）的一个标志。原纤蛋白-1是ECM中微原纤维的主要成分，可能在SSc的发病机制中起作用。SSc的TSK1小鼠模型存在原纤蛋白-1基因（FBN1）的框内重复，这导致产生一种比正常蛋白更大且更易被蛋白水解的蛋白。对人类SSc皮肤成纤维细胞中原纤蛋白-1的代谢标记研究表明，虽然合成的原纤蛋白-1量正常，但该蛋白本身似乎不稳定。此外，在SSc患者和TSK1小鼠的血清中已证实存在针对原纤蛋白-1的自身抗体。特别是，在患有弥漫性和局限性硬皮病或CREST（钙质沉着、雷诺现象、食管运动障碍、指（趾）硬皮病、毛细血管扩张）综合征的日本患者中观察到高频率的抗原纤蛋白-1。对使用微卫星标记患病率高的美洲原住民群体进行的基因研究表明，FBN1单倍型与SSc之间存在强关联。随后，对FBN1单核苷酸多态性（SNP）的研究表明，某些FBN1单倍型在患有局限性硬皮病的美洲原住民和日本患者中均与SSc相关。因此，对22例日本SSc患者的FBN1进行测序，以确定是否存在任何相关突变或SNP。序列分析揭示了8个编码SNP和14个非编码SNP以及其他多态性。其中，外显子A的5'非翻译区的CT插入与疾病呈显著负相关。
