Abstract:Background
Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications.
Methods
We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas … Show more
“… 14 – 18 Moreover, except for various neoplasms, GSTM3 is also reported to exert an important function in other kinds of diseases, such as Alzheimer’s disease, cataracts, neurocysticercosis, cystic fibrosis, and Brugada syndrome. 19 – 24 Figure 1 Gene cluster of GSTM1-5 arranged as 5ʹ-GSTM4-M2-M1-M5-M3-3ʹ and mutations of GSTM3 on chromosome 1p13. 3.…”
Cancer is a major cause of human mortality; however, the molecular mechanisms and proteomic biomarkers that cause tumor progression in malignant tumors are either unknown or only partially revealed. Glutathione S-transferases mu3 (GSTM3), which belongs to a family of xenobiotic detoxifying phase II enzymes, is associated with carcinogen detoxification and the metabolism of exogenous electrophilic substances. It has been reported that GSTM3 has different polymorphisms in various tumor cells and regulates tumorigenesis, cell invasion, metastasis, chemoresistance, and oxidative stress. Deep research into the regulatory mechanisms involved in disorders of GSTM3 expression and the function of GSTM3 in different cancers may facilitate improvements in cancer prevention and targeted therapy. The combination of GSTM3 with other family members can regulate the carcinogenesis and susceptibility to different cancers in humans. GSTM3 also regulates the reactive oxygen species (ROS) and participates in oxidative stress-mediated pathology. Here, we provide a general introduction to GSTM3 in order to better understand the role of GSTM3 in cancer.
“… 14 – 18 Moreover, except for various neoplasms, GSTM3 is also reported to exert an important function in other kinds of diseases, such as Alzheimer’s disease, cataracts, neurocysticercosis, cystic fibrosis, and Brugada syndrome. 19 – 24 Figure 1 Gene cluster of GSTM1-5 arranged as 5ʹ-GSTM4-M2-M1-M5-M3-3ʹ and mutations of GSTM3 on chromosome 1p13. 3.…”
Cancer is a major cause of human mortality; however, the molecular mechanisms and proteomic biomarkers that cause tumor progression in malignant tumors are either unknown or only partially revealed. Glutathione S-transferases mu3 (GSTM3), which belongs to a family of xenobiotic detoxifying phase II enzymes, is associated with carcinogen detoxification and the metabolism of exogenous electrophilic substances. It has been reported that GSTM3 has different polymorphisms in various tumor cells and regulates tumorigenesis, cell invasion, metastasis, chemoresistance, and oxidative stress. Deep research into the regulatory mechanisms involved in disorders of GSTM3 expression and the function of GSTM3 in different cancers may facilitate improvements in cancer prevention and targeted therapy. The combination of GSTM3 with other family members can regulate the carcinogenesis and susceptibility to different cancers in humans. GSTM3 also regulates the reactive oxygen species (ROS) and participates in oxidative stress-mediated pathology. Here, we provide a general introduction to GSTM3 in order to better understand the role of GSTM3 in cancer.
“…Recently, patients affected by BrS carrying a gross deletion of the GSTM3 gene showed higher rates of syncope and SCD compared to those without, suggesting a novel potential genetic modifier/risk predictor for the development of BrS. However, further studies should be done to clarify the role of this CNV in BrS [ 14 ]. Then, focusing only in SCN5A , CNVs appear to underlie no more than 1% of diagnosed BrS cases.…”
Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the SCN5A gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome.
“…In the transparent zebrafish larvae, complementary fluorescence imaging of the whole heart as a method to functionally assess ICAs has been used in LQTS [53,82,104,105], SQTS [106] and cardiac conduction-system disease (CCSD) ( Table 2) [107]. ECG recordings or (high-speed) light microscopy videos (i.e., monitoring heart rate) of non-transparent adult zebrafish have been utilised for the study of LQTS [54,108,109], SQTS [69] and BrS [110]. Most recent development and implementation of state-of-the-art fluorescence microscopy techniques and GEFIs enable reliable in vivo optical mapping in the whole heart of zebrafish larvae [85,101,103].…”
Section: Optical Mapping In Hipsc-cm and Zebrafish To Model Icasmentioning
Inherited cardiac arrhythmias contribute substantially to sudden cardiac death in the young. The underlying pathophysiology remains incompletely understood because of the lack of representative study models and the labour-intensive nature of electrophysiological patch clamp experiments. Whereas patch clamp is still considered the gold standard for investigating electrical properties in a cell, optical mapping of voltage and calcium transients has paved the way for high-throughput studies. Moreover, the development of human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) has enabled the study of patient specific cell lines capturing the full genomic background. Nevertheless, hiPSC-CMs do not fully address the complex interactions between various cell types in the heart. Studies using in vivo models, are therefore necessary. Given the analogies between the human and zebrafish cardiovascular system, zebrafish has emerged as a cost-efficient model for arrhythmogenic diseases. In this review, we describe how hiPSC-CM and zebrafish are employed as models to study primary electrical disorders. We provide an overview of the contemporary electrophysiological phenotyping tools and discuss in more depth the different strategies available for optical mapping. We consider the current advantages and disadvantages of both hiPSC-CM and zebrafish as a model and optical mapping as phenotyping tool and propose strategies for further improvement. Overall, the combination of experimental readouts at cellular (hiPSC-CM) and whole organ (zebrafish) level can raise our understanding of the complexity of inherited cardiac arrhythmia disorders to the next level.
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