Amyloidosis Center and ‡Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, Massachusetts 02118, United States.
J Proteome Res. 2017 Nov 3;16(11):4104-4112. doi: 10.1021/acs.jproteome.7b00479. Epub 2017 Sep 27.
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) that 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 as well as 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.
转甲状腺素蛋白（TTR）通常是一种在血浆中循环的蛋白，它可能会发生错误折叠和聚集，最终导致淀粉样纤维在细胞外沉积，通常靶向心脏或神经组织。这种疾病被称为转甲状腺素相关淀粉样变性（ATTR），如果不治疗，它通常具有致命性。ATTR 是由 TTR 基因突变引起的淀粉样变变体 TTR 蛋白（ATTRm）引起的，经典地被称为家族性淀粉样心肌病（FAC）或家族性淀粉样多发性神经病（FAP），反映了临床表型。由于没有疾病的确切生物标志物，因此 FAC 和 FAP 是难以诊断的病理学；此外，缺乏疾病特异性进展的衡量标准，并且治疗选择有限。因此，发现疾病的敏感和特异性指标有可能改善识别能力，能够准确测量淀粉样变的进展和对治疗的反应，并揭示 FAC 和 FAP 病理生物学机制的关键信息。在这项研究中，目标是研究与 ATTRm 相关的 FAC 和 FAP 类型的独特的血清蛋白质组学特征。多反应监测质谱（MRM-MS）是一种用于蛋白质组分析的强大技术，用于测量来自 FAC 和 FAP 患者样本中的 160 种蛋白质的血清浓度。结果与从年龄（≥60 岁）、性别（男性）和种族（白种人）匹配的个体中获得的健康对照血清的数据进行了比较。ATTRm（FAC 和 FAP）和对照样本的蛋白质组学分析显示，在所研究的 192 种血清蛋白中的 107 种（56%）中，浓度存在显著差异。在比较 FAC 与 FAP 时，发现几种蛋白质的浓度差异以及相互作用和功能是每种疾病所特有的；TTR 的水平明显较低，是 FAC 所特有的，但不是 FAP 所特有的。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 共有的术语。相反，二硫键是 FAC 所特有的；分泌、糖基化位点：N-连接、糖基化、糖蛋白、多态性和序列变体仅与 FAP 相关。在 FAC 中预测的蛋白质-蛋白质关联见于反应、结合和激活过程；在 FAP 中没有发现关联。这项研究表明，ATTRm 患者和对照血清之间存在显著的蛋白质组学差异，以及与 TTR 等几种蛋白质的循环水平相关的 ATTRm 表型变异。鉴定出 FAC 和 FAP 特有的血清蛋白可能具有诊断和预后效用，并可能为疾病机制提供重要线索。
