Identification of rare heterozygous linkage R965C‐R1309H mutations in the pore‐forming region of SCN5A gene associated with complex arrhythmia

Lin, Yenn‐Jiang; Qin, Jiading; Shen, Yifeng; Huang, Jiana; Zhang, Zuoquan; Zhu, Zhiling; Lü, Huifang; Huang, Ying; Yin, Yuelan; Wang, Ani; Jin, Lizi; Hu, Zhenyu; Lin, Xiufang; Jiang, Bin

doi:10.1002/mgg3.1613

Cited by 5 publications

(2 citation statements)

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“…According to previous studies, abnormal desmosome genetic expressions, including desmocollin-2 (DSC2), desmoglein-2 (DSG2), plakophilin-2 (PKP2), desmoplakin (DSP), plakoglobin (JUP) and desmin (DES) participate in the pathogenic mechanism of arrhythmogenic cardiomyopathy (ACM) [17,18,20,[24][25][26][27]. Interestingly, loss-of-function of SCN5A mutations induced complex arrhythmia, including Brs, atrial fibrillation (AF), atrial standstill, VT and sick sinus syndrome [28]. In this study, we first discovered some interesting interactions among desmosome proteins and cardiac sodium channels in cardiomyocytes, including DSG2 and Na v 1.5 (α subunit of the sodium channel, encoded by SCN5A), PKP2 and Na v 1.5, DES and Na v 1.5, NEBL and DES in the cardiac desmosomes, through literature research using "NEBL and SCN5A (or Na v 1.5, or sodium channel), nebulette and SCN5A (or Na v 1.5, or sodium channel), each protein of desmosomes (including DSG2, DSC2, PKP2 and DSP) and NEBL (or nebulette), each protein of desmosomes (including DSG2, DSC2, PKP2 and DSP) and SCN5A (or Na v 1.5, or sodium channel), NEBL (or nebulette) and Brugada syndrome, each protein of desmosomes (including DSG2, DSC2, PKP2 and DSP) and Brugada syndrome" in the NCBI PubMed database.…”

Section: Literature Summary Of Nebl and Scn5a Interactionmentioning

confidence: 98%

Whole exome sequencing in Brugada and long QT syndromes revealed novel rare and potential pathogenic mutations related to the dysfunction of the cardiac sodium channel

Chen

Guo

et al. 2022

Orphanet J Rare Dis

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Background Brugada syndrome (Brs) and long QT syndrome (LQTs) are the most observed “inherited primary arrhythmia syndromes” and “channelopathies”, which lead to sudden cardiac death. Methods Detailed clinical information of Brs and LQTs patients was collected. Genomic DNA samples of peripheral blood were conducted for whole-exome sequencing on the Illumina HiSeq 2000 platform. Then, we performed bioinformatics analysis for 200 genes susceptible to arrhythmias and cardiomyopathies. Protein interaction and transcriptomic co-expression were analyzed using the online website and GTEx database. Results All sixteen cases of Brs and six cases of LQTs were enrolled in the current study. Four Brs carried known pathogenic or likely pathogenic of single-point mutations, including SCN5A p.R661W, SCN5A p.R965C, and KCNH2 p.R692Q. One Brs carried the heterozygous compound mutations of DSG2 p.F531C and SCN5A p.A1374S. Two Brs carried the novel heterozygous truncated mutations (MAF < 0.001) of NEBL (p.R882X) and NPPA (p.R107X), respectively. Except for the indirect interaction between NEBL and SCN5A, NPPA directly interacts with SCN5A. These gene expressions had a specific and significant positive correlation in myocardial tissue, with high degrees of co-expression and synergy. Two Brs carried MYH7 p.E1902Q and MYH6 p.R1820Q, which were predicted as "damaging/possibly damaging" and "damaging/damaging" by Polyphen and SIFT algorithm. Two LQTs elicited the pathogenic single splicing mutation of KCNQ1 (c.922-1G > C). Three LQTs carried a single pathogenic mutation of SCN5A p.R1880H, KCNH2 p.D161N, and KCNQ1 p.R243S, respectively. One patient of LQTs carried a frameshift mutation of KCNH2 p. A188Gfs*143. Conclusions The truncated mutations of NEBL (p.R882X) and NPPA (p.R107X) may induce Brugada syndrome by abnormally affecting cardiac sodium channel. SCN5A (p.R661W, p.R965C and p.A1374S) and KCNH2 (p.R692Q) may cause Brugada syndrome, while SCN5A (p.R1880H), KCNQ1 (c.922-1G > C and p.R243S) and KCNH2 (p.D161N and p.A188Gfs*143) may lead to long QT syndrome.

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Section: Literature Summary Of Nebl and Scn5a Interactionmentioning

confidence: 98%

Whole exome sequencing in Brugada and long QT syndromes revealed novel rare and potential pathogenic mutations related to the dysfunction of the cardiac sodium channel

Chen

Guo

et al. 2022

Orphanet J Rare Dis

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“…In families with affected subjects, the main channels to be mutated in SSS are Nav1.5 and HCN, whose genes SCN5A and HCN are responsible for the generation of I Na and I f currents, as observed by genetic screening [144][145][146][147][148][149][150]. It is noteworthy to mention that I Na alterations are not only manifest in SSS, but also in other cardiac arrhythmias and might often generate a mixed clinical picture (as an example, [151,152]).…”

Section: Sss Due To Genetic Mutationsmentioning

confidence: 99%

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

Iop

Iliceto

Civieri

et al. 2021

Cells

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Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena.

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Biophysical mechanisms of myocardium sodium channelopathies

Zaytseva,

Kulichik,

Kostareva

et al. 2024

Pflugers Arch - Eur J Physiol

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Identification of rare heterozygous linkage R965C‐R1309H mutations in the pore‐forming region of SCN5A gene associated with complex arrhythmia

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 5 publications

References 10 publications

Whole exome sequencing in Brugada and long QT syndromes revealed novel rare and potential pathogenic mutations related to the dysfunction of the cardiac sodium channel

Whole exome sequencing in Brugada and long QT syndromes revealed novel rare and potential pathogenic mutations related to the dysfunction of the cardiac sodium channel

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

Biophysical mechanisms of myocardium sodium channelopathies

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