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Serum Proteomic Variability Associated with Clinical Phenotype in Familial Transthyretin Amyloidosis (ATTRm)
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2017-09-18 00:00:00 , DOI: 10.1021/acs.jproteome.7b00479
Gloria G. Chan 1 , Clarissa M. Koch 1 , Lawreen H. Connors 1
Affiliation  

Transthyretin (TTR), normally a plasma circulating protein, can become misfolded and aggregated, ultimately leading to extracellular deposition of amyloid fibrils usually targeted to heart or nerve tissues. Referred to as TTR-associated amyloidoses (ATTR), this group of diseases is frequently life threatening and fatal if untreated. ATTR, caused by amyloid-forming variant TTR proteins (ATTRm) which arise from point mutations in the TTR gene, were classically referred to as familial amyloid cardiomyopathy (FAC) or familial amyloid polyneuropathy (FAP) reflecting the clinical phenotype. FAC and FAP are pathologies that can be challenging to diagnose as there are no definitive biomarkers of disease; moreover, disease-specific measures of progression are lacking and treatment options are limited. Thus, the discovery of sensitive and specific indicators of disease has the potential to improve recognition, enable accurate measurement of amyloid progression and response to treatment, and reveal key information regarding FAC and FAP pathobiological mechanisms. In this study, the goal was to investigate serum proteomic features unique to FAC and FAP types of ATTRm. Multiple-reaction monitoring mass spectrometry (MRM-MS), a powerful technique in profiling proteomes, was used to measure the serum concentrations of 160 proteins in samples from FAC and FAP patients. Results were compared to data from healthy control sera obtained from individuals matched to age (≥ 60 years), gender (male), and race (Caucasian). Proteomic analyses of ATTRm (FAC and FAP) and control samples showed significant concentration differences in 107 of 192 (56%) of the serum proteins that were studied. In comparing FAC to FAP, differences in concentrations, and interactions and functions of several proteins were identified as unique to each disease; significantly lower levels of TTR were specific to FAC, but not to FAP. Annotated functional clustering identified extracellular region, signal and signal peptide as terms common to FAC and FAP. Conversely, disulfide bond was unique to FAC; secreted, glycosylation site:N-linked, glycosylation, glycoprotein, polymorphism, and sequence variant were associated solely with FAP. Predicted protein-protein associations in FAC were seen for reaction, binding, and activation processes; no associations were found in FAP. This study demonstrates significant proteomic differences between ATTRm patient and control sera, as well as ATTRm phenotype-associated variations in the circulating levels of several proteins including TTR. The identification of serum proteins unique to FAC and FAP may have diagnostic and prognostic utility, and could possibly provide important clues about disease mechanisms.

中文翻译:

家族性甲状腺素运甲状腺素蛋白淀粉样变性病(ATTRm)的临床表型与血清蛋白质组学变异性相关。

运甲状腺素蛋白(TTR),通常是血浆循环蛋白,可能会错误折叠并聚集,最终导致通常靶向心脏或神经组织的淀粉样蛋白原纤维在细胞外沉积。被称为与TTR相关的淀粉样蛋白(ATTR),这一类疾病通常威胁生命,如果不加以治疗,将会致命。由TTR基因中点突变产生的形成淀粉样变的TTR蛋白(ATTRm)引起的ATTR,通常被称为反映临床表型的家族性淀粉样心肌病(FAC)或家族性淀粉样多发性神经病(FAP)。由于没有明确的疾病生物标志物,FAC和FAP是难以诊断的病理学。此外,缺乏针对疾病进展的措施,并且治疗选择受到限制。因此,发现疾病的敏感和特定指标有可能提高识别度,能够准确测量淀粉样蛋白的进展和对治疗的反应,并揭示有关FAC和FAP病理生物学机制的关键信息。在这项研究中,目标是研究FAC和FAP类型的ATTRm特有的血清蛋白质组学特征。多重反应监测质谱(MRM-MS)是一种功能强大的蛋白质组分析技术,用于测量FAC和FAP患者样品中160种蛋白质的血清浓度。将结果与健康对照血清的数据进行比较,该数据来自与年龄(≥60岁),性别(男性)和种族(白种人)匹配的个体。对ATTRm(FAC和FAP)和对照样品的蛋白质组学分析显示,在所研究的192个血清蛋白中有107个(56%)存在显着的浓度差异。在将FAC与FAP进行比较时,几种蛋白质的浓度差异以及相互作用和功能被确定为每种疾病所独有。TTR的水平显着降低是针对FAC的,而不是针对FAP的。带注释的功能聚类确定了细胞外区域,信号和信号肽是FAC和FAP的通用术语。相反,二硫键是FAC所独有的;分泌的糖基化位点:N-连接,糖基化,糖蛋白,多态性和序列变异仅与FAP相关。在FAC中,预测的蛋白-蛋白缔合可以观察到反应,结合和激活过程。在FAP中未发现任何关联。这项研究证明了ATTRm患者和对照血清之间蛋白质组学上的显着差异,以及ATTRm表型相关的几种蛋白质(包括TTR)的循环水平变化。鉴定FAC和FAP特有的血清蛋白可能具有诊断和预后作用,并可能提供有关疾病机制的重要线索。
更新日期:2017-09-19
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