Formation of a TBX20-CASZ1 protein complex is protective against dilated cardiomyopathy and critical for cardiac homeostasis

Kennedy, Leslie; Kaltenbrun, Erin; Greco, Todd M.; Temple, Brenda; Herring, Laura E.; Cristea, Ileana M.; Conlon, Frank L.

doi:10.1371/journal.pgen.1007011

Cited by 25 publications

(27 citation statements)

References 84 publications

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“…The assembly of proteins into macromolecular complexes is known to represent functional units within the proteome and to facilitate numerous biological processes, including those essential for cardiac function [43–46]. To expand our investigation of the heart proteome and begin to address the potential of differential abundances in cardiac proteins across species, we next aimed to predict which cardiac protein complexes are shared or unique between these model species.…”

Section: Resultsmentioning

confidence: 99%

Conservation and divergence of protein pathways in the vertebrate heart

et al. 2019

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Heart disease is the leading cause of death in the western world. Attaining a mechanistic understanding of human heart development and homeostasis and the molecular basis of associated disease states relies on the use of animal models. Here, we present the cardiac proteomes of 4 model vertebrates with dual circulatory systems: the pig (Sus scrofa), the mouse (Mus musculus), and 2 frogs (Xenopus laevis and Xenopus tropicalis). Determination of which proteins and protein pathways are conserved and which have diverged within these species will aid in our ability to choose the appropriate models for determining protein function and to model human disease. We uncover mammalian- and amphibian-specific, as well as species-specific, enriched proteins and protein pathways. Among these, we find and validate an enrichment in cell-cycle–associated proteins within Xenopus laevis. To further investigate functional units within cardiac proteomes, we develop a computational approach to profile the abundance of protein complexes across species. Finally, we demonstrate the utility of these data sets for predicting appropriate model systems for studying given cardiac conditions by testing the role of Kielin/chordin-like protein (Kcp), a protein found as enriched in frog hearts compared to mammals. We establish that germ-line mutations in Kcp in Xenopus lead to valve defects and, ultimately, cardiac failure and death. Thus, integrating these findings with data on proteins responsible for cardiac disease should lead to the development of refined, species-specific models for protein function and disease states.

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Section: Resultsmentioning

confidence: 99%

Conservation and divergence of protein pathways in the vertebrate heart

et al. 2019

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“…CASZ1 is required to directly regulate an EGFL7/RhoA-mediated pathway to promote vertebrate vascular development 27 and plays a key role in cardiac homeostasis and dilated cardiomyopathy. 28 The association between CASZ1 methylations and IS has not been reported. The newly identified methylations locate in the CpG Island, which overlaps the promoter in the 5′ region of CASZ1 (figure e-1, links.lww.com/NXG/A313 ).…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis identifies the association between CASZ1 methylation and ischemic stroke

Zhang

Wang

et al. 2020

Neurol Genet

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ObjectiveTo highlight potential epigenetic risk factors for blood pressure (BP) and ischemic stroke (IS) in loci identified by genome-wide association studies (GWASs).MethodsWe detected DNA methylation for BP (317,756 individuals from UK Biobank) and IS (521,612 individuals from MEGASTROKE) in Europeans by using the summary data–based mendelian randomization (SMR) method. We selected the most relevant gene to validate the association in 1,207 patients with hypertensive IS and 1,269 controls from the Chinese populations.ResultsWe first identified 173 CpG sites in 90 genes, 337 CpG sites in 142 genes, and 9 CpG sites in 7 genes that were significantly associated with systolic, diastolic BP, and IS, respectively. The methylation level of cg12760995 in CASZ1 was associated with systolic (PSMR = 1.74 × 10−12), diastolic BP (PSMR = 2.48 × 10−10), and IS (odds ratio [OR] = 0.92 [95% confidence interval [CI]: 0.91–0.94]; PSMR = 2.28 × 10−8) in Europeans. The methylation levels of 17 sites in the promoter of CASZ1 were measured in the Chinese individuals, and 10 of them were significantly associated with IS. The higher methylation level of CASZ1 was associated with a lower risk of IS (adjusted OR = 0.97 [95% CI: 0.96–0.99]). CASZ1 seemed to be hypomethylated in hypertensive cases, and the level was negatively correlated with BP. Systolic and diastolic BP mediated approximately 61.2% (p = 3.49 × 10−6) and 45.0% (p = 0.0029) of the association between CASZ1 methylation and IS, respectively.ConclusionsThis study identified DNA methylations that were associated with BP and IS. CASZ1 was hypomethylated in Chinese patients with hypertensive IS.

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“…A polygenic influence (ie, the background genetic variation in individuals) leading to variable expression of overt cardiomyopathy with arrhythmias cannot be discounted and would require further studies. [27][28][29][30] Other genes have been well described to have significant concomitant dilated cardiomyopathy and rhythm disturbance, either or both of which can lead to significant clinical disease, sudden death, or the need for heart transplantation. Arguably the best described to date is lamin A/C defects.…”

Section: Discussionmentioning

confidence: 99%

Clinical characterisation of a novel SCN5A variant associated with progressive malignant arrhythmia and dilated cardiomyopathy

et al. 2019

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Introduction:The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest.Methods:A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing.Results:All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination.Conclusions:There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.

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Formation of a TBX20-CASZ1 protein complex is protective against dilated cardiomyopathy and critical for cardiac homeostasis

Cited by 25 publications

References 84 publications

Conservation and divergence of protein pathways in the vertebrate heart

Conservation and divergence of protein pathways in the vertebrate heart

Integrative analysis identifies the association between CASZ1 methylation and ischemic stroke

Clinical characterisation of a novel SCN5A variant associated with progressive malignant arrhythmia and dilated cardiomyopathy

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