Medicine Department, School of Medicine, Institute of Research and Innovation in Biomedical Sciences (INiBICA), University of Cádiz, Cádiz, Spain.
Cardiology Department, Institute of Research and Innovation in Biomedical Sciences (INiBICA), Puerto Real University Hospital, Cádiz, Spain.
J Mol Med (Berl). 2018 Aug;96(8):845-856. doi: 10.1007/s00109-018-1666-1. Epub 2018 Jul 14.
Lamin A/C gene (LMNA)-related familial dilated cardiomyopathy (fDCM) is an aggressive heart disease that often leads to transplantation and sudden death. The aim of our study was to evaluate the circulating microRNA (miRNA) profiles of patients with LMNA pathogenic mutations. The study population (N = 75) included (i) patients with pathogenic LMNA mutations responsible for fDCM (LMNA), (ii) age- and sex-matched LMNA wild-type controls (LMNA control), and (iii) LMNA wild-type idiopathic DCM (iDCM) patients (LMNA iDCM). Detailed clinical information was obtained from each participant. A panel of 179 plasma miRNAs was evaluated using RT-qPCR. An initial screening study was performed in LMNA carriers and age-matched LMNA controls (N = 16). Forty-four miRNAs were specifically deregulated in LMNA carriers. Ten miRNA candidates were selected for subsequent validation after coexpression analyses and filtered for expression levels and statistical significance. Among the candidates, let-7a-5p, miR-142-3p, miR-145-5p and miR-454-3p levels were significantly increased in LMNA carriers compared to LMNA controls and iDCM patients (P < 0.050). These circulating miRNAs, and their combination, were also associated with the presence of pathogenic mutations in regression and ROC analyses. This signature also discriminates between LMNA healthy subjects and LMNA carriers who are phenotypically negative for DCM and between LMNA iDCM and LMNA-related DCM patients. Correlation and functional enrichment analyses supported their association with the pathophysiology of the disease. We demonstrated for the first time that a specific miRNA signature could serve as a novel non-invasive tool to assist in the diagnosis of patients with fDCM caused by LMNA pathogenic mutations. KEY MESSAGES: Let-7a-5p, miR-142-3p, miR-145-5p and miR-454-3p are differentially expressed in LMNA carriers. A composite score based on these miRNAs is a biomarker of mutations in the LMNA gene. This miRNA signature can be associated with the pathophysiology of familial DCM. The circulating miRNA profile can assist in the diagnosis of familial DCM.
lamin A/C 基因（LMNA）相关家族性扩张型心肌病（fDCM）是一种侵袭性心脏病，常导致移植和猝死。我们的研究目的是评估携带 LMNA 致病性突变患者的循环 microRNA（miRNA）谱。研究人群（N=75）包括（i）由 LMNA 致病性突变引起的 fDCM 患者（LMNA），（ii）年龄和性别匹配的 LMNA 野生型对照（LMNA 对照），和（iii）LMNA 野生型特发性扩张型心肌病（iDCM）患者（LMNA iDCM）。从每位参与者那里获得详细的临床信息。使用 RT-qPCR 评估了一组 179 种血浆 miRNA。在 LMNA 携带者和年龄匹配的 LMNA 对照（N=16）中进行了初步筛选研究。在 LMNA 携带者中，有 44 种 miRNA 特异性下调。经过 coexpression 分析和表达水平及统计学意义筛选后，选择了 10 个 miRNA 候选物进行后续验证。在候选物中，与 LMNA 对照和 iDCM 患者相比，let-7a-5p、miR-142-3p、miR-145-5p 和 miR-454-3p 的水平在 LMNA 携带者中显着升高（P<0.050）。在回归和 ROC 分析中，这些循环 miRNA 及其组合也与致病性突变的存在相关。该特征还可以区分 LMNA 健康受试者和表型上无 DCM 的 LMNA 携带者，以及 LMNA iDCM 和 LMNA 相关 DCM 患者。相关性和功能富集分析支持它们与疾病病理生理学的关联。我们首次证明，特定的 miRNA 特征可作为一种新的非侵入性工具，辅助诊断由 LMNA 致病性突变引起的 fDCM 患者。
let-7a-5p、miR-142-3p、miR-145-5p 和 miR-454-3p 在 LMNA 携带者中表达差异。
基于这些 miRNA 的组合评分是 LMNA 基因突变的生物标志物。
该 miRNA 特征可与家族性 DCM 的病理生理学相关联。
循环 miRNA 谱可辅助家族性 DCM 的诊断。
