A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels

Furtado, Milena B.; Wilmanns, Julia C.; Chandran, Anjana; Tonta, Mary A; Biben, Christine; Eichenlaub, Michael P.; Coleman, Harold A.; Berger, Silke; Bouveret, Romaric; Singh, Ramesh; Harvey, Richard P.; Ramialison, Mirana; Pearson, James T.; Parkington, Helena C.; Rosenthal, Nadia; Costa, Mauro W.

doi:10.1016/j.diff.2015.12.003

Cited by 25 publications

(29 citation statements)

References 43 publications

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“…Heterozygous mutations in NKX2-5 are associated with a spectrum of congenital heart diseases (CHDs) in humans and mice (27)(28)(29)(30)(31). NKX2-5 also has been shown to regulate a number of target genes involved in the cardiomyocyte action potential, suggesting that it may play a direct role in AF predisposition (32).…”

Section: Resultsmentioning

confidence: 99%

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Laforest¹,

Dai²,

Tyan³

et al. 2019

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Laforest¹,

Dai²,

Tyan³

et al. 2019

Journal of Clinical Investigation

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“…High levels of ETV1 are detectable in the heart, brain, and lung, while expression levels are low in skeletal tion in Nkx2-5 RNA and protein levels specifically in atrial and Purkinje myocytes, which resulted in a corresponding approximately 50% reduction in Cx40 levels and VCS hypoplasia. Cx40 is a known direct transcriptional target of NKX2-5 (8,60) and responds in a dose-dependent manner (9). Etv1-null mice displayed structural and functional defects of the VCS that phenocopy Nkx2-5 haploinsufficient mice (18,44).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor ETV1 is essential for rapid conduction in the heart

Shekhar¹,

Lin²,

Liu³

et al. 2016

Journal of Clinical Investigation

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Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart.

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“…LRRC10 has been recognized as a cardiac-specific transcriptional target gene of Nkx2.5 [14], which regulates cardiac ion channels, including Nav1.5 (encoded by SCN5A gene), Cav1.2 (encoded by CACNA1C gene), and ERG (encoded by KCNH2 gene) [15]. Dysfunction of these cardiac ion channels are all linked to BrS and even sudden cardiac death [16–21].…”

Section: Discussionmentioning

confidence: 99%

“…For example, PKP2 (gene related to ARVC) missense mutations that cause sodium current deficit could yield a BrS phenotype, even in the absence of overt structural feature characteristic of ARVC [11], and SCN5A (gene linked to BrS) missense mutations have been reported in DCM patients [12, 13]. Moreover, LRRC10 has been recognized as a cardiac-specific transcriptional target gene of Nkx2.5 [14], which transcriptionally regulates cardiac ion channels, including Nav1.5, Cav1.2, and ERG [15]. Dysfunction of these cardiac ion channels are all associated with BrS and even sudden cardiac death [16–21].…”

Section: Introductionmentioning

confidence: 99%

Molecular pathological study on LRRC10 in sudden unexplained nocturnal death syndrome in the Chinese Han population

et al. 2016

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Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Clinical features of SUNDS survivors suggested that SUNDS is similar to Brugada syndrome (BrS). Leucine-rich repeat containing 10 (LRRC10) gene was a newly identified gene linked to dilated cardiomyopathy, a disease associated with sudden cardiac death. To investigate the prevalence and spectrum of genetic variants of LRRC10 gene in SUNDS and BrS, the coding regions of LRRC10 were genetically screened in 113 sporadic SUNDS victims (from January 2005 to December 2015, 30.7 ± 7.5 years) and ten BrS patients (during January 2010 to December 2014, 38.7 ± 10.3 years) using direct Sanger sequencing. Afterwards, LRRC10 missense variant carriers were screened for a panel of 80 genes known to be associated with inherited cardiac arrhythmia/cardiomyopathy using target-captured next-generation sequencing. In this study, an in silico-predicted malignant LRRC10 mutation p.E129K was detected in one SUNDS victim without pathogenic rare variant in a panel of 80 arrhythmia/cardiomyopathy-related genes. We also provided evidence to show that rare variant p.P69L might contribute to the genetic cause for one SUNDS victim and two BrS family members. This is the first report of genetic screening of LRRC10 in Chinese SUNDS victims and BrS patients. LRRC10 may be a new susceptible gene for SUNDS, and LRRC10 variant was initially and genetically linked to BrS-associated arrhythmia.

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A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels

Cited by 25 publications

References 43 publications

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Transcription factor ETV1 is essential for rapid conduction in the heart

Molecular pathological study on LRRC10 in sudden unexplained nocturnal death syndrome in the Chinese Han population

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