Circulating microRNAs profile in patients with transthyretin variant amyloidosis

Transthyretin variant amyloidosis (ATTRv) is a rare autosomal dominant disease characterized by the accumulation of amyloid in many organs, mostly causing a sensory-motor neuropathy, cardiomyopathy, and dysautonomia. The aim of the study was to report microRNAs (miRNAs) expression profile identified in the blood of ATTRv patients. 10 symptomatic ATTRv patients, 10 asymptomatic carriers of transthyretin variant (TTRv), 10 patients with Charcot-Marie-Tooth (CMT) disease, and 10 healthy controls were studied. Human Schwann cells cultures were used to study the regulatory effects of miR-150-5p on the expression of cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF). ATTRv patients had 33 miRNAs up-regulated and 48 down-regulated versus healthy controls; 9 miRNAs were up-regulated and 30 down-regulated versus CMT patients; 19 miRNAs were up-regulated and 38 down-regulated versus asymptomatic TTRv carriers. Twelve out of the 19 upregulated miRNAs had a fold increase higher than 100. The validation experiment indicated miR-150-5p as a valuable biomarker to differentiate ATTRv patients from asymptomatic TTRv carriers (AUC: 0.9728; p<0.0001). Schwann cells culture model demonstrated that miR-150-5p is a powerful negative regulator of CREB, BDNF and NGF genes. Identification of deregulated miRNAs can help in understanding the complex pathomechamism underlying the development of ATTRv and related multisystemic pathology. Further investigations are needed on the role of circulating miR-150-5p to predict the shift of TTRv carriers from an asymptomatic status to symptoms appearance. We investigated serum miRNA expression in 10 symptomatic ATTRv patients, 10 asymptomatic TTRv patients, 10 CMT patients and 10 unaffected controls (CTRL)

转甲状腺素蛋白变体淀粉样变性（Transthyretin variant amyloidosis, ATTRv）是一种罕见的常染色体显性遗传病，以多器官淀粉样蛋白沉积为特征，主要引发感觉运动神经病、心肌病及自主神经功能障碍。本研究旨在鉴定ATTRv患者血液中的微小核糖核酸（microRNAs, miRNAs）表达谱。共纳入10例有症状ATTRv患者、10例转甲状腺素蛋白变体（transthyretin variant, TTRv）无症状携带者、10例夏科-马里-图思病（Charcot-Marie-Tooth, CMT）患者以及10名健康对照者开展研究。采用人施万细胞（Schwann cells）培养模型，探究miR-150-5p对环磷酸腺苷反应元件结合蛋白（cAMP response element-binding protein, CREB）、脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）以及神经生长因子（nerve growth factor, NGF）表达的调控作用。与健康对照相比，ATTRv患者有33种miRNA上调、48种miRNA下调；与CMT患者相比，ATTRv患者有9种miRNA上调、30种miRNA下调；与无症状TTRv携带者相比，ATTRv患者有19种miRNA上调、38种miRNA下调。其中19种上调miRNA中有12种的表达倍数高于100。验证实验结果显示，miR-150-5p可作为区分ATTRv患者与无症状TTRv携带者的有效生物标志物（AUC：0.9728；p<0.0001）。施万细胞培养模型实验证实，miR-150-5p是CREB、BDNF及NGF基因的强效负调控因子。鉴定异常表达的miRNA有助于阐明ATTRv及其相关多系统病变发生发展的复杂致病机制。后续仍需进一步研究循环miR-150-5p的作用，以预测TTRv携带者从无症状状态进展为症状出现阶段的风险。本研究检测了10例有症状ATTRv患者、10例无症状TTRv患者、10例CMT患者以及10名未受影响对照者（CTRL）的血清miRNA表达水平。