The Role of TRPM4 Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution

Palladino, Alberto; Papa, Andrea Antonio; Petillo, Roberta; Scutifero, Marianna; Morra, Salvatore; Passamano, Luigia; Nigro, Vincenzo; Politano, Luisa

doi:10.3390/genes13020258

Cited by 12 publications

(7 citation statements)

References 37 publications

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“…TRPM4 heterozygous mutations are linked to isolated cardiac conduction disorders and progressive familial heart block type I. 11 RANGRF codes for Ran Guanin Nucleotide Release Factor and regulates the expression and function of the Nav1.5 cardiac sodium channel in humans. 12 RANGRF mutations were related to BS and histiocytoid cardiomyopathy in the literature.…”

Section: Discussionmentioning

confidence: 99%

“…TRPM4 is expressed predominantly in cardiac and smooth muscle cells. TRPM4 heterozygous mutations are linked to isolated cardiac conduction disorders and progressive familial heart block type I 11 . RANGRF codes for Ran Guanin Nucleotide Release Factor and regulates the expression and function of the Nav1.5 cardiac sodium channel in humans 12 .…”

Section: Discussionmentioning

confidence: 99%

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From Death to Life/Back to the Future: Detailed Premorbid Clinical and Family History Can Save Lives and Address the Final Diagnosis in Sudden Unexplained Deaths With Negative Autopsy

Turkgenc,

Baydar,

Deniz

et al. 2023

Applied Immunohistochemistry &Amp; Molecular Morphology

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Sudden cardiac death is a sudden, unexpected death developed by one of the many different causes of cardiac arrest that occur within 1 hour of the onset of new symptoms. Sudden unexplained death (SUD) comprises a normal heart at postmortem examination and negative toxicological analysis. SUD often arises from cardiac genetic disease, particularly channelopathies. Channelopathies, or inherited arrhythmia syndromes, are a group of disorders characterized by an increased risk of sudden cardiac death, abnormal cardiac electrical function, and, typically, a structurally normal heart. They share an underlying genetic etiology where disease-causing genetic variants may lead to the absence or dysfunction of proteins involved in the generation and propagation of the cardiac action potential. Our study aimed to evaluate the importance of next-generation sequencing in the postmortem investigations of SUD cases. In this study, 5 forensic SUD cases were investigated for inherited cardiac disorders. We screened a total of 68 cardiac genes for the sibling of case 1, as well as case 2, and 51 genes for cases 3, 4, and 5. Of the 12 variants identified, 2 likely pathogenic variants (16.7%) were the TMEM43_ c.1000+2T>C splice site mutation and the SCN5A_ p.W703X nonsense mutation. The remaining 10 variants of uncertain significance were detected in the TRPM4, RANGRF, AKAP9, KCND3, KCNE1, DSG2, CASQ1, and SNTA1 genes. Irrespective of genetic testing, all SUD families require detailed clinical testing to identify relatives who may be at risk. Molecular autopsy and detailed premorbid clinical and family histories can survive family members of SUD cases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

From Death to Life/Back to the Future: Detailed Premorbid Clinical and Family History Can Save Lives and Address the Final Diagnosis in Sudden Unexplained Deaths With Negative Autopsy

Turkgenc,

Baydar,

Deniz

et al. 2023

Applied Immunohistochemistry &Amp; Molecular Morphology

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“…Clinical studies have reported a strong link between TRPM4 genetic variants and cardiac conduction disorders (Kecskes et al, 2015 ; Liu et al, 2013 ; Palladino et al, 2022 ; Stallmeyer et al, 2012 ). Experimental studies have revealed similar findings in mouse models (Demion et al, 2014 ; Guinamard et al, 2006 ; Liu et al, 2010 ; Mathar et al, 2010 , 2014 ; Pironet et al, 2019 ) using different Trpm4 −/− mouse models.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex‐ and age‐dependent manner in mice

Arullampalam,

Essers,

Boukenna

et al. 2023

Physiological Reports

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TRPM4 is a calcium‐activated, voltage‐modulated, nonselective ion channel widely expressed in various cells and tissues. TRPM4 regulates the influx of sodium ions, thus playing a role in regulating the membrane potential. In the heart, TRPM4 is expressed in both cardiomyocytes and cells of the conductive pathways. Clinical studies have linked TRPM4 mutations to several cardiac disorders. While data from experimental studies have demonstrated TRPM4's functional significance in cardiac physiology, its exact roles in the heart have remained unclear. In this study, we investigated the role of TRPM4 in cardiac physiology in a newly generated Trpm4 knockdown mouse model. Male and female Trpm4 knockdown (Trpm4−/−) and wild‐type mice of different ages (5‐ to 12‐ week‐old (young) and 24‐week‐old or more (adult)) were characterized using a multimodal approach, encompassing surface electrocardiograms (ECG), echocardiography recordings, ex vivo ECGs in isolated heart, endocardial mappings, Western blots, and mRNA quantifications. The assessment of cardiac electrophysiology by surface ECGs revealed no significant differences between wild‐type and Trpm4−/− young (5‐ to 12‐week‐old) mice of either sex. Above 24 weeks of age, adult male Trpm4−/− mice showed reduced heart rate and increased heart rate variability. Echocardiography revealed that only adult male Trpm4−/− mice exhibited slight left ventricular hypertrophic alterations compared to controls, illustrated by alterations of the mitral valve pressure halftime, the mitral valve E/A ratio, the isovolumetric relaxation time, and the mitral valve deceleration. In addition, an assessment of the right ventricular systolic function by scanning the pulmonary valve highlighted an alteration in pulmonary valve peak velocity and pressure in adult male Trpm4−/− mice. Endocardial mapping recordings showed that applying 5 μM of the new TRPM4 inhibitor NBA triggered a third‐degree atrioventricular block on 40% of wild‐type hearts. These results confirm the key role of TRPM4 in the proper structure and electrical function of the heart. It also reveals differences between male and female animals that have never been reported. In addition, the investigation of the effects of NBA on heart function confirms the role of TRPM4 in atrioventricular conduction.

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“…Clinical studies have reported a strong link between TRPM4 genetic variants and cardiac conduction disorders (Kecskes et al 2015, Liu, Chatel, Simard, Syam, Salle, Probst, Morel, Millat, Lopez, Abriel, Schott, Guinamard and Bouvagnet 2013, Palladino et al 2022, Stallmeyer, Zumhagen, Denjoy, Duthoit, Hebert, Ferrer, Maugenre, Schmitz, Kirchhefer, Schulze-Bahr and Guicheney 2012). Experimental studies have revealed similar findings in mouse models (Demion, Thireau, Gueffier, Finan, Khoueiry, Cassan, Serafini, Aimond, Granier, Pasquie, Launay and Richard 2014, Guinamard et al 2006, Liu, El Zein, Kruse, Guinamard, Beckmann, Bozio, Kurtbay, Megarbane, Ohmert, Blaysat, Villain, Pongs and Bouvagnet 2010, Mathar et al 2014, Mathar, Vennekens, Meissner, Kees, Van der Mieren, Camacho Londono, Uhl, Voets, Hummel, van den Bergh, Herijgers, Nilius, Flockerzi, Schweda and Freichel 2010, Pironet et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex- and age-dependent manner in mice

Arullampalam

Essers

Rougier

et al. 2022

Preprint

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Background: TRPM4 is a calcium-activated, voltage-modulated, non-selective ion channel widely expressed in various types of cells and tissues. TRPM4 regulates the influx of sodium ions, thus playing a role in regulating the membrane potential. In the heart, TRPM4 is expressed in both cardiomyocytes and cells of the conductive pathways. Clinical studies have linked TRPM4 mutations to several cardiac disorders. While data from experimental studies have demonstrated TRPM4's functional significance in cardiac physiology, its exact roles in the heart remain unclear. Aim: To investigate the role of TRPM4 in cardiac physiology in a newly generated knockdown Trpm4 mouse model. Methods and results: Male and female Trpm4 knockdown (Trpm4 -/-) and wild-type mice 5- to 12-weeks-old (young) or 24-week-old or more (adult) were characterized using a multimodal approach, encompassing surface electrocardiograms (ECG), echocardiography recordings, pseudo and intracardiac ECGs, western blots, and mRNA quantifications. The assessment of cardiac electrophysiology by surface ECGs revealed no significant differences between wild type and Trpm4 -/- 5- to 12-weeks-old mice of either sex. Above 24 weeks of age, adult male Trpm4 -/- mice showed significantly reduced heart rate and increased heart rate variability. Echocardiography reveals that only adult male Trpm4 -/- mice exhibited slight left ventricular hypertrophic alterations with an alteration of the mitral valve pressure half time, the mitral valve E/A ratio, the isovolumetric relaxation time, and the mitral valve deceleration. In addition, an assessment of the right ventricular systolic function by scanning the pulmonary valve highlighted an alteration in pulmonary valve peak velocity and pressure in male Trpm4 -/- adult mice. Finally, intracardiac ECG recordings showed that the application of 5-micromolar NBA triggered a third-degree atrioventricular block on 40% of wild-type hearts only. Conclusions: These results confirm the important role of TRPM4 in the proper structure and electrical function of the heart. It also reveals significant differences between male and female animals that have never been reported before. In addition, the investigation of the effects of NBA on heart function highlights the role of TRPM4 in atrioventricular conduction and provides the first evidence showing the efficacy of this compound on native cardiac tissues.

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The Role of TRPM4 Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution

Cited by 12 publications

References 37 publications

From Death to Life/Back to the Future: Detailed Premorbid Clinical and Family History Can Save Lives and Address the Final Diagnosis in Sudden Unexplained Deaths With Negative Autopsy

From Death to Life/Back to the Future: Detailed Premorbid Clinical and Family History Can Save Lives and Address the Final Diagnosis in Sudden Unexplained Deaths With Negative Autopsy

Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex‐ and age‐dependent manner in mice

Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex- and age-dependent manner in mice

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