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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Proteomics of specific treatment-related alterations in Fabry disease: A strategy to identify biological abnormalities
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Proteomics of specific treatment-related alterations in Fabry disease: A strategy to identify biological abnormalities

机译：法布里病中与治疗相关的特定改变的蛋白质组学：一种识别生物学异常的策略

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摘要

Fabry disease is inherited as an X-linked disorder secondary to deficiency of α-galactosidase A, resulting in abnormal metabolism of substances containing α-D-galactosyl moieties. As a consequence, a multisystem disorder develops, culminating in strokes, progressive renal, and cardiac dysfunction. Signs and symptoms of Fabry disease become manifest in childhood, but diagnosis is often delayed. Thirteen children with Fabry disease (age range, 6.5-17 years) were studied as part of a 6-month open-label study of enzyme replacement therapy (ERT) with agalsidase alfa. Paired serum samples were drawn at the start of the study and after 6 months of ERT. Global protein changes in paired samples were compared by using differential stable isotope labeling of peptide lysine residues with O-methylisourea and subsequent nanoHPLC-tandem MS. Statistically significant decreases were observed for five proteins following ERT: α_2-HS glycoprotein, vitamin D-binding protein, transferrin, Ig-α-2 C chain, and α-2-antiplasmin. The presence of low levels of α-2-antiplasmin and plasminogen was confirmed by alternate means in 34 consecutive patients, including four of five ERT-naieve subjects. Decreased α-2-antiplasmin was associated with a parallel increase in circulating VEGF. Soluble VEGF receptor-2 was significantly elevated in plasma of patients compared with pediatric controls and decreased with ERT. These results suggest previously unknown abnormalities of fibrinolysis and angiogenesis factors in Fabry disease. We demonstrated the feasibility of identifying treatment-specific alterations in a small number of subjects that point to previously unsuspected disease-related biological abnormalities.
机译：法布里病是继α-半乳糖苷酶A缺乏后继发的X连锁疾病，导致含有α-D-半乳糖基部分的物质代谢异常。结果，发展成多系统障碍，最终导致中风，进行性肾脏和心脏功能障碍。法布里氏病的体征和症状在儿童时期就很明显，但诊断通常会延迟。作为一项为期6个月的开放式研究，研究人员对13名患有法布里疾病的儿童进行了试验，这些研究都是用阿加糖酶α进行的酶替代疗法（ERT）的研究。在研究开始时和ERT六个月后抽取配对的血清样品。通过使用O-甲基异脲对肽赖氨酸残基进行差异稳定同位素标记和随后的nanoHPLC-串联MS，比较了配对样品中的总蛋白质变化。在ERT后的5种蛋白质中观察到统计学显着的下降：α_2-HS糖蛋白，维生素D结合蛋白，转铁蛋白，Ig-α-2C链和α-2-抗纤溶酶。通过交替的方法，在34例连续的患者中证实了低水平的α-2-抗纤溶酶和纤溶酶原的存在，其中包括5名ERT初免的受试者中的4名。 α-2-antiplasmin的减少与循环VEGF的平行增加有关。与小儿对照相比，患者血浆中可溶性VEGF受体2显着升高，而ERT则降低。这些结果表明在法布里病中纤维蛋白溶解和血管生成因子的先前未知的异常。我们证明了在少数受试者中指出先前未曾怀疑的疾病相关生物学异常的治疗特异性改变的可行性。

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