Department of Biomedical and Anatomical Sciences, New York Institute of Technology College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR 72401, USA.
Arkansas Biosciences Institute, Jonesboro, AR 72401, USA.
Cells. 2023 Oct 3;12(19):2398. doi: 10.3390/cells12192398.
Hundreds of thousands of people die each year as a result of sudden cardiac death, and many are due to heart rhythm disorders. One of the major causes of these arrhythmic events is Brugada syndrome, a cardiac channelopathy that results in abnormal cardiac conduction, severe life-threatening arrhythmias, and, on many occasions, death. This disorder has been associated with mutations and dysfunction of about two dozen genes; however, the majority of the patients do not have a definite cause for the diagnosis of Brugada Syndrome. The protein-coding genes represent only a very small fraction of the mammalian genome, and the majority of the noncoding regions of the genome are actively transcribed. Studies have shown that most of the loci associated with electrophysiological traits are located in noncoding regulatory regions and are expected to affect gene expression dosage and cardiac ion channel function. Noncoding RNAs serve an expanding number of regulatory and other functional roles within the cells, including but not limited to transcriptional, post-transcriptional, and epigenetic regulation. The major noncoding RNAs found in Brugada Syndrome include microRNAs; however, others such as long noncoding RNAs are also identified. They contribute to pathogenesis by interacting with ion channels and/or are detectable as clinical biomarkers. Stem cells have received significant attention in the recent past, and can be differentiated into many different cell types including those in the heart. In addition to contractile and relaxational properties, BrS-relevant electrophysiological phenotypes are also demonstrated in cardiomyocytes differentiated from stem cells induced from adult human cells. In this review, we discuss the current understanding of noncoding regions of the genome and their RNA biology in Brugada Syndrome. We also delve into the role of stem cells, especially human induced pluripotent stem cell-derived cardiac differentiated cells, in the investigation of Brugada syndrome in preclinical and clinical studies.
每年有数十万人因心源性猝死而死亡，其中许多是由于心律紊乱。这些心律失常事件的主要原因之一是 Brugada 综合征，这是一种心脏通道病，导致异常的心脏传导、严重的危及生命的心律失常，并且在许多情况下导致死亡。这种疾病与大约二十几种基因的突变和功能障碍有关；然而，大多数患者的 Brugada 综合征诊断没有明确的原因。蛋白质编码基因仅代表哺乳动物基因组的一小部分，而基因组的大多数非编码区域都在转录。研究表明，与电生理特征相关的大多数基因座位于非编码调控区域，预计会影响基因表达剂量和心脏离子通道功能。非编码 RNA 在细胞内发挥越来越多的调节和其他功能作用，包括但不限于转录、转录后和表观遗传调控。Brugada 综合征中发现的主要非编码 RNA 包括 microRNAs；然而，也发现了其他非编码 RNA，如长非编码 RNA。它们通过与离子通道相互作用或作为临床生物标志物可检测到，从而导致发病机制。干细胞在最近受到了广泛关注，可以分化为许多不同的细胞类型，包括心脏细胞。除了收缩和松弛特性外，还在由成人细胞诱导的干细胞分化而来的心肌细胞中显示出与 BrS 相关的电生理表型。在这篇综述中，我们讨论了基因组非编码区域及其在 Brugada 综合征中的 RNA 生物学的当前理解。我们还深入探讨了干细胞，特别是人类诱导多能干细胞衍生的心脏分化细胞，在临床前和临床研究中对 Brugada 综合征的研究中的作用。
