Deficient Zebrafish
            <i>Ether-à-Go-Go</i>
            –Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish
            <i>Reggae</i>
            Mutants

Hassel, David; Scholz, Eberhard P.; Trano, Nicole; Friedrich, Oliver; Just, Steffen; Meder, Benjamin; Weiß, Daniel L.; Zitron, Edgar; Marquart, Sabine; Vogel, Britta; Karle, Christoph A.; Seemann, Gunnar; Fishman, Mark C.; Katus, Hugo A.; Rottbauer, Wolfgang

doi:10.1161/circulationaha.107.752220

Cited by 111 publications

(94 citation statements)

References 28 publications

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“…Pharmacological inhibition of the zERG channel normalized the phenotype. This model confirms the association between increased repolarization and SQTS and the application of the model may aid in defining a pharmacological treatment of SQTS [Hassel et al, 2008]. A spontaneous animal model of SQTS that is currently not genetically characterized is seen in the red kangaroo, where a short QT c interval is found and sudden death is very common [Campbell, 1989].…”

Section: Overview Of the Pathogenetic Mechanismsupporting

confidence: 67%

The genetic basis of long QT and short QT syndromes: A mutation update

et al. 2009

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Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS-and SQTS-associated mutations.

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Section: Overview Of the Pathogenetic Mechanismsupporting

confidence: 67%

The genetic basis of long QT and short QT syndromes: A mutation update

et al. 2009

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“…S1B-G; supplementary material Movie 1). To examine whether, similar to the situation in the zebrafish mutants island beat and reggae (Hassel et al, 2008;Rottbauer et al, 2001), disturbed cardiac excitation is responsible for cardiac acontractility in fla, we next monitored calcium transients in fla hearts by high-resolution fluorescent microscopy. However, similar to the situation in wildtype hearts, in fla hearts a calcium wave commenced in the sinus venosus region, then migrated through the atrium and then the ventricle of the non-beating fla heart (supplementary material Fig.…”

Section: Resultsmentioning

confidence: 99%

The myosin-interacting protein SMYD1 is essential for sarcomere organization

et al. 2011

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SummaryAssembly, maintenance and renewal of sarcomeres require highly organized and balanced folding, transport, modification and degradation of sarcomeric proteins. However, the molecules that mediate these processes are largely unknown. Here, we isolated the zebrafish mutant flatline (fla), which shows disturbed sarcomere assembly exclusively in heart and fast-twitch skeletal muscle. By positional cloning we identified a nonsense mutation within the SET-and MYND-domain-containing protein 1 gene (smyd1) to be responsible for the fla phenotype. We found SMYD1 expression to be restricted to the heart and fast-twitch skeletal muscle cells. Within these cell types, SMYD1 localizes to both the sarcomeric M-line, where it physically associates with myosin, and the nucleus, where it supposedly represses transcription through its SET and MYND domains. However, although we found transcript levels of thick filament chaperones, such as Hsp90a1 and UNC-45b, to be severely upregulated in fla, its histone methyltransferase activity -mainly responsible for the nuclear function of SMYD1 -is dispensable for sarcomerogenesis. Accordingly, sarcomere assembly in fla mutant embryos can be reconstituted by ectopically expressing histone methyltransferase-deficient SMYD1. By contrast, ectopic expression of myosinbinding-deficient SMYD1 does not rescue fla mutants, implicating an essential role for the SMYD1-myosin interaction in cardiac and fast-twitch skeletal muscle thick filament assembly.

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“…Genetic mapping; positional cloning; RNA antisense in situ hybridization; immunostaining; MO, mRNA, and plasmid injection procedures 15 ; functional assessment; protein structure prediction; and statistical analysis are described in the expanded Materials and Methods section in the online data supplement, available at http://circres.ahajournals.org.…”

Section: Methodsmentioning

confidence: 99%

A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo

Meder

Laufer

Hassel

et al. 2009

Circulation Research

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Abstract-Although it is well known that mutations in the cardiac essential myosin light chain-1 (cmlc-1) gene can cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of cMLC-1 in the heart are only poorly understood. We have isolated the zebrafish mutant lazy susan (laz), which displays severely reduced contractility of both heart chambers. By positional cloning, we identified a nonsense mutation within the zebrafish cmlc-1 gene to be responsible for the laz phenotype, leading to expression of a carboxyl-terminally truncated cMLC-1. Whereas complete loss of cMLC-1 leads to cardiac acontractility attributable to impaired cardiac sarcomerogenesis, expression of a carboxyl-terminally truncated cMLC-1 in laz mutant hearts is sufficient for normal cardiac sarcomerogenesis but severely impairs cardiac contractility in a cell-autonomous fashion. Whereas overexpression of wild-type cMLC-1 restores contractility of laz mutant cardiomyocytes, overexpression of phosphorylation site serine 195-deficient cMLC-1 (cMLC-1 S195A ) does not reconstitute cardiac contractility in laz mutant cardiomyocytes. By contrast, introduction of a phosphomimetic amino acid on position 195 (cMLC-1 S195D ) rescues cardiomyocyte contractility, demonstrating for the first time an essential role of the carboxyl terminus and especially of serine 195 of cMLC-1 in the regulation of cardiac contractility. Key Words: zebrafish Ⅲ genetics Ⅲ essential cardiac myosin light chain-1 Ⅲ phosphorylation Ⅲ myocardial contractility M utations in the cardiac essential myosin light chain (cMLC) have been linked for some time to human hypertrophic cardiomyopathy, the leading cause of premature death in the young. 1 However, the precise in vivo structural and functional roles of essential MLCs in the heart are still not well understood. Dissecting their biological role in mammals is especially complicated by the fact that in the mammalian heart at least 2 different essential MLC isoforms (ELCv, which is expressed mainly in ventricles and slow skeletal muscle; and ELCa, which is expressed in atria and ventricles during development and restrictedly expressed in atria in the adult) are coexpressed and can at least partially compensate for each others function. 2 In contrast to mice and humans, in zebrafish only 1 isoform of essential MLC is expressed in the heart. Loss of cardiac essential MLC function in mice leads to early embryonic lethality attributable to impaired mesoderm development, whereas morpholino (MO) knockdown studies in zebrafish recently revealed an essential function of cMLC-1 in cardiomyocyte sarcomerogenesis. 3,4 Both essential and regulatory MLCs bind to the neck region of myosin heavy chains (MHCs) and contain calciumbinding EF-hand motifs and hence might modulate the calcium sensitivity of cross-bridge cycling, thereby fine tuning cardiac contractility. Phosphorylation of cardiac regulatory MLCs at a unique serine on position 19 by MLC kinase (MLCK) can induce conformational changes and endorse myosin-actin ...

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Deficient Zebrafish Ether-à-Go-Go –Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants

Cited by 111 publications

References 28 publications

The genetic basis of long QT and short QT syndromes: A mutation update

The genetic basis of long QT and short QT syndromes: A mutation update

The myosin-interacting protein SMYD1 is essential for sarcomere organization

A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo

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