A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice

Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca2+ homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2)-mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca2+ sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca2+-dependent pathway for AF risk.

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Characterization of branchial transepithelial calcium fluxes in freshwater trout, Salmo gairdneri

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1988.254.3.r491 ◽

1988 ◽

Vol 254 (3) ◽

pp. R491-R498 ◽

Cited By ~ 14

Author(s):

S. F. Perry ◽

G. Flik

Keyword(s):

Active Transport ◽

Calcium Uptake ◽

Chloride Cells ◽

Salmo Gairdneri ◽

Apical Surface ◽

Electrochemical Gradient ◽

Plasma Membrane Vesicles ◽

Pavement Cells ◽

Calcium Fluxes

Experiments were performed to determine whether gill transepithelial calcium fluxes in the freshwater trout (Salmo gairdneri) are passive or require active transport and to characterize the mechanisms involved. A comparison of the in vivo unidirectional flux ratios with the flux ratios calculated according to the transepithelial electrochemical gradients revealed that calcium uptake from the water requires active transport of Ca2+. The inhibition of calcium uptake by external lanthanum, the specific deposition of lanthanum on the apical surface of chloride cells, and the favorable electrochemical gradient for calcium across the apical membrane suggest that the initial step in branchial calcium uptake is the passive entry of calcium into the cytosol of chloride cells through apical channels that are permeable to calcium. The study of gill basolateral plasma membrane vesicles demonstrated the existence of a high-affinity calmodulin-dependent calcium-transporting system [half-maximal Ca2+ concentration (K0.5) = 160 nM, Vmax = 1.86 nmol.min-1.mg protein-1]. This system actively transports calcium from the cytosol of chloride cells into the plasma against a sizeable electrochemical gradient, thereby completing the transepithelial uptake of calcium. Calcium efflux occurs passively through paracellular pathways between chloride cells and adjacent pavement cells or between neighboring pavement cells.

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A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice

Scientific Reports ◽

10.1038/s41598-020-74800-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Kensuke Ihara ◽

Tetsuo Sasano ◽

Yuichi Hiraoka ◽

Marina Togo-Ohno ◽

Yurie Soejima ◽

...

Keyword(s):

Atrial Fibrillation ◽

Dilated Cardiomyopathy ◽

Missense Mutation ◽

Cardiac Dysfunction ◽

Ventricular Arrhythmias ◽

Left Ventricular ◽

Mutant Mice ◽

Clinical State ◽

Missense Mutations ◽

Nuclear Localization Signals

Abstract Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over 60 genes, including RBM20, which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. RBM20S637A protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes.

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Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—short QT syndrome

10.1093/med/9780198784906.003.0150 ◽

2018 ◽

Author(s):

Erol Tülümen ◽

Martin Borggrefe

Keyword(s):

Atrial Fibrillation ◽

Genetic Basis ◽

Association Studies ◽

Single Gene ◽

Candidate Gene Approach ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Short Qt Syndrome ◽

Dispersion Of Repolarization ◽

Qt Syndrome

Short QT syndrome (SQTS) is a very rare, sporadic or autosomal dominant inherited channelopathy characterized by abnormally short QT intervals on the electrocardiogram and increased propensity to atrial and ventricular tachyarrhythmias and/or sudden cardiac death. Since its recognition as a distinct clinical entity in 2000, significant progress has been made in defining the clinical, molecular, and genetic basis of SQTS. To date, several causative gain-of-function mutations in potassium channel genes and loss-of-function mutations in calcium channel genes have been identified. The physiological consequence of these mutations is an accelerated repolarization, thus abbreviated action potentials and shortened QT interval with an increased inhomogeneity and dispersion of repolarization. Regarding other rare monogenetic arrhythmias, a genetic basis of atrial fibrillation was considered very unlikely until very recently. However, in the last decade the heritability of atrial fibrillation in the general population has been well described in several epidemiological studies. So far, more than 30 genes have been implicated in atrial fibrillation through candidate gene approach studies, and 14 loci were found to be associated with atrial fibrillation through genome-wide association studies. This genetic heterogeneity and the low prevalence of mutations in any single gene restrict the clinical utility of genetic screening in atrial fibrillation.

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Formal proof of the requirement of MESP1 and MESP2 in mesoderm specification and their transcriptional control via specific enhancers in mice

Development ◽

10.1242/dev.194613 ◽

2021 ◽

Vol 148 (20) ◽

Author(s):

Rieko Ajima ◽

Yuko Sakakibara ◽

Noriko Sakurai-Yamatani ◽

Masafumi Muraoka ◽

Yumiko Saga

Keyword(s):

Binding Sites ◽

Transcriptional Control ◽

Formal Proof ◽

T Box ◽

Mesoderm Specification ◽

Mesoderm Formation ◽

Quadruple Mutant ◽

Heart Formation ◽

Polarity Regulation ◽

Dose Dependent

ABSTRACT MESP1 and MESP2 are transcriptional factors involved in mesoderm specification, somite boundary formation and somite polarity regulation. However, Mesp quadruple mutant zebrafish displayed only abnormal somite polarity without mesoderm specification defects. In order to re-evaluate Mesp1/Mesp2 mutants in mice, Mesp1 and Mesp2 single knockouts (KOs), and a Mesp1/Mesp2 double KO were established using genome-editing techniques without introducing selection markers commonly used before. The Mesp1/Mesp2 double KO embryos exhibited markedly severe mesoderm formation defects that were similar to the previously reported Mesp1/Mesp2 double KO embryos, indicating species differences in the function of MESP family proteins. However, the Mesp1 KO did not display any phenotype, including heart formation defects, which have been reported previously. We noted upregulation of Mesp2 in the Mesp1 KO embryos, suggesting that MESP2 rescues the loss of MESP1 in mesoderm specification. We also found that Mesp1 and Mesp2 expression in the early mesoderm is regulated by the cooperation of two independent enhancers containing T-box- and TCF/Lef-binding sites. Deletion of both enhancers caused the downregulation of both genes, resulting in heart formation defects. This study suggests dose-dependent roles of MESP1 and MESP2 in early mesoderm formation.

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Uncovering the Genetic Basis of Sleep: Use of Clock Mutant Mice

10.21236/ada396387 ◽

2001 ◽

Author(s):

Fred W. Turek ◽

Martha H. Vitatema

Keyword(s):

Genetic Basis ◽

Mutant Mice ◽

Clock Mutant

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Common themes emerge in the transcriptional control of T helper and developmental cell fate decisions regulated by the T-box, GATA and ROR families

Immunology ◽

10.1111/j.1365-2567.2008.03040.x ◽

2009 ◽

Vol 126 (3) ◽

pp. 306-315 ◽

Cited By ~ 35

Author(s):

Sara A. Miller ◽

Amy S. Weinmann

Keyword(s):

Cell Fate ◽

Transcriptional Control ◽

T Helper ◽

T Box ◽

Cell Fate Decisions

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Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—short QT syndrome

ESC CardioMed ◽

10.1093/med/9780198784906.003.0150_update_001 ◽

2018 ◽

pp. 676-679

Author(s):

Erol Tülümen ◽

Martin Borggrefe

Keyword(s):

Atrial Fibrillation ◽

Genetic Basis ◽

Association Studies ◽

Single Gene ◽

Epidemiological Studies ◽

Candidate Gene Approach ◽

Loss Of Function ◽

Short Qt Syndrome ◽

Qt Intervals ◽

Qt Syndrome

Short QT syndrome (SQTS) is a very rare, sporadic or autosomal dominant inherited channelopathy characterized by abnormally short QT intervals on the electrocardiogram and increased propensity to atrial and ventricular tachyarrhythmias and/or sudden cardiac death. Since its recognition as a distinct clinical entity in 2000, significant progress has been made in defining the clinical, molecular, and genetic basis of SQTS. To date, several causative gain-of-function mutations in potassium channel genes and loss-of-function mutations in calcium channel genes have been identified. The physiological consequence of these mutations is an accelerated repolarization, thus abbreviated action potentials and shortened QT interval with an increased inhomogeneity and dispersion of repolarization. Regarding other rare monogenetic arrhythmias, a genetic basis of atrial fibrillation was considered very unlikely until very recently. However, in the last decade the heritability of atrial fibrillation in the general population has been well described in several epidemiological studies. So far, more than 30 genes have been implicated in atrial fibrillation through candidate gene approach studies, and more than 25 loci were found to be associated with atrial fibrillation through genome-wide association studies. This genetic heterogeneity and the low prevalence of mutations in any single gene restrict the clinical utility of genetic screening in atrial fibrillation.

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