Fibrillins are the major components of microfibrils in the extracellular matrix of elastic and non-elastic tissues. They are multi-domain proteins, containing primarily calcium binding epidermal growth factor-like (cbEGF) domains and 8-cysteine/transforming growth factor-beta binding protein-like (TB) domains. Mutations in the fibrillin-1 gene give rise to Marfan syndrome, a connective tissue disorder with clinical complications in the cardiovascular, skeletal, ocular and other organ systems. Here, we review the consequences of engineered Marfan syndrome mutations in fibrillin-1 at the protein, cellular and organismal levels. Representative point mutations associated with Marfan syndrome in affected individuals have been introduced and analyzed in recombinant fibrillin-1 fragments. Those mutations affect fibrillin-1 on a structural and functional level. Mutations which impair folding of cbEGF domains can affect protein trafficking. Protein folding disrupted by some mutations can lead to defective secretion in mutant fibrillin-1 fragments, whereas fragments with other Marfan mutations are secreted normally. Many Marfan mutations render fibrillin-1 more susceptible to proteolysis. There is also evidence that some mutations affect heparin binding. Few mutations have been further analyzed in mouse models. An extensively studied mouse model of Marfan syndrome expresses mouse fibrillin-1 with a missense mutation (p.C1039G). The mice display similar characteristics to human patients with Marfan syndrome. Overall, the analyses of engineered mutations leading to Marfan syndrome provide important insights into the pathogenic molecular mechanisms exerted by mutated fibrillin-1.

中文翻译：

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导致马凡氏综合征的原纤维蛋白1的工程突变作用于蛋白质，细胞和有机体水平。

原纤维蛋白是弹性和非弹性组织的细胞外基质中微纤维的主要成分。它们是多结构域蛋白，主要包含钙结合表皮生长因子样（cbEGF）域和8半胱氨酸/转化生长因子-β结合蛋白样（TB）域。fibrillin-1基因的突变会引起马凡氏综合症，这是一种结缔组织疾病，在心血管，骨骼，眼部和其他器官系统中具有临床并发症。在这里，我们审查了在蛋白质，细胞和有机体水平上原纤维1的马凡氏综合症基因工程突变的后果。已在重组原纤维蛋白-1片段中引入并分析了受影响个体中与马凡综合症相关的代表性点突变。这些突变在结构和功能水平上影响原纤维蛋白-1。损害cbEGF结构域折叠的突变会影响蛋白质运输。被某些突变破坏的蛋白质折叠会导致突变的原纤维蛋白-1片段分泌缺陷，而具有其他马凡突变的片段则正常分泌。许多Marfan突变使fibrillin-1更易于蛋白水解。也有证据表明某些突变会影响肝素结合。在小鼠模型中很少有突变被进一步分析。广泛研究的Marfan综合征小鼠模型表达了带有错义突变的小鼠原纤维蛋白1（p.C1039G）。小鼠表现出与患有马凡氏综合症的人类患者相似的特征。全面的，