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首页> 美国卫生研究院文献>The Journal of Clinical Investigation >Quantitative differences in biosynthesis and extracellular deposition of fibrillin in cultured fibroblasts distinguish five groups of Marfan syndrome patients and suggest distinct pathogenetic mechanisms.
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Quantitative differences in biosynthesis and extracellular deposition of fibrillin in cultured fibroblasts distinguish five groups of Marfan syndrome patients and suggest distinct pathogenetic mechanisms.

机译：在培养的成纤维细胞中原纤维蛋白的生物合成和胞外沉积的数量差异区分了五组马凡氏综合症患者并提出了不同的致病机制。

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Pulse-chase studies of [35S]cysteine-labeled fibrillin were performed on fibroblast strains from 55 patients with Marfan syndrome (MFS), including 13 with identified mutations in the fibrillin-1 gene and 10 controls. Quantitation of the soluble intracellular and insoluble extracellular fibrillin allowed discrimination of five groups. Groups I (n = 8) and II (n = 19) synthesize reduced amounts of normal-sized fibrillin, while synthesis is normal in groups III (n = 6), IV (n = 18), and V (n = 4). When extracellular fibrillin deposition is measured, groups I and III deposit between 35 and 70% of control values, groups II and IV < 35%, and group V > 70%. A deletion mutant with a low transcript level from the mutant allele and seven additional patients have the group I protein phenotype. Disease in these patients is caused by a reduction in microfibrils associated with either a null allele, an unstable transcript, or an altered fibrillin product synthesized in low amounts. In 68% of the MFS individuals (groups II and IV), a dominant negative effect is invoked as the main pathogenetic mechanism. Products made by the mutant allele in these fibroblasts are proposed to interfere with microfibril formation. Insertion, deletion, and exon skipping mutations, resulting in smaller fibrillin products, exhibit the group II phenotype. A truncated form of fibrillin of 60 kD was identified with specific fibrillin antibodies in one of the group II cell culture media. Seven of the nine known missense mutations, giving rise to abnormal, but normal-sized fibrillin molecules, are in group IV.
机译：[55S]半胱氨酸标记的原纤维蛋白的脉冲追踪研究是针对55名马凡氏综合症（MFS）患者的成纤维细胞株进行的，其中包括13例原纤维蛋白-1基因突变和10名对照。可溶性细胞内和不溶性细胞外原纤维蛋白的定量分析可分为五组。第I组（n = 8）和第II组（n = 19）合成了正常大小的原纤维蛋白，而第III组（n = 6），IV（n = 18）和V（n = 4）的合成是正常的。当测量细胞外原纤维蛋白沉积时，I组和III组沉积在对照值的35％至70％之间，II组和IV组＜35％，而V组＞ 70％。来自突变体等位基因的转录水平较低的缺失突变体和另外7名患者具有I组蛋白表型。这些患者的疾病是由于与无效等位基因，不稳定的转录本或合成的低浓度原纤维蛋白产物相关的微纤维减少引起的。在68％的MFS个体（II和IV组）中，主要的负面作用被称为主要的致病机制。建议在这些成纤维细胞中由突变等位基因制得的产物会干扰微原纤维的形成。插入，删除和外显子跳过突变，导致较小的原纤维蛋白产物，表现出第二组表型。在第II组细胞培养基之一中，用特异的原纤维蛋白抗体鉴定出60 kD的截短形式的原纤维蛋白。 IV组中有9个已知的错义突变中的7个，会引起异常但正常大小的原纤维蛋白分子。

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