Publications by authors named "David Y Chiang"
Article Synopsis
- Brugada syndrome, primarily caused by loss-of-function variants, has only about 20% of cases explained by known genetic factors; recent studies point to the role of microtubule dynamics in the syndrome.
- Researchers used CRISPR/Cas9 to create a knockout zebrafish model and conducted various experiments like voltage mapping, ECG, and immunocytochemistry to evaluate cardiac function.
- Findings showed that knockout hearts had impaired electrical activity and disorganized cell junctions, with a notable improvement when adjusting microtubule dynamics through targeted interventions.
Article Synopsis
- Hox genes are crucial for defining segments in the muscular circulatory system of invertebrates, but it's challenging to link these segments to the vertebrate heart, especially regarding abnormalities seen in patients with HOXB gene deletions.
- Researchers used CRISPR to create a zebrafish model with a deletion in the hoxbb cluster, resulting in significant heart issues, including heart failure and atrioventricular regurgitation by day five.
- Further analysis showed that the deletion of the hoxb1b gene specifically led to these cardiac problems, suggesting it is a key player in regulating heart development by influencing other genes involved in the atrioventricular boundary.
Article Synopsis
- Protein-protein interactions are key to cellular functions and signaling, and understanding these networks helps in interpreting disease-related gene variants, particularly in the context of ion channels.
- The study identifies and validates the functional roles of ten interactors for 13 types of ion channels in murine cardiac tissue, using various genetic techniques and microscopy.
- A computational framework was developed to reconstruct human ion channel networks from deep proteome and gene expression data, revealing that 44% of the proteins in the network are significantly linked to electrocardiogram (ECG) traits, enhancing our understanding of cardiac electrophysiology.
Article Synopsis
- - Atrial standstill (AS) is a rare condition marked by lack of electrical activity in the heart's atria, and this study aims to explore its clinical features, genetic causes, and patient outcomes.
- - The research involved 20 patients diagnosed with AS at an average age of 6.6 years, revealing a high prevalence of arrhythmias (80%) and significant cardiac events, including cardiac arrests in 4 patients.
- - Genetic testing showed SCN5A variants in 65% of patients, indicating that these variants may contribute to AS; patients unable to pace their atria face increased risks for blood clots, emphasizing the need for anticoagulant treatment.
Article Synopsis
- Brugada syndrome (BrS) is a serious heart condition linked to sudden death in young adults, with few known genetic factors beyond the SCN5A gene.
- A large study involving 2,820 BrS cases and 10,001 controls revealed 21 genetic signals across 12 locations, suggesting a strong genetic component to the disorder.
- Key findings highlight the importance of transcription regulation in BrS development and introduce microtubule-related mechanisms that affect the expression of a key cardiac protein, shedding light on the disorder's genetic and molecular basis.
Hyperphosphorylation of the calcium release channel/ryanodine receptor type 2 (RyR2) at serine 2814 (S2814) is associated with multiple cardiac diseases including atrial fibrillation and heart failure. Despite recent advances, the molecular mechanisms driving pathological changes associated with RyR2 S2814 phosphorylation are still not well understood. Using affinity-purification coupled to mass spectrometry (AP-MS), we investigated the RyR2 interactome in ventricles from wild-type (WT) mice and two S2814 knock-in mutants: the unphosphorylated alanine mutant (S2814A) and hyperphosphorylated mimic aspartic acid mutant (S2814D).
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- The QT interval is a measure of heart's electrical activity, and previous studies linked genetic variants affecting it to LITAF, a protein involved in regulating cell function.
- The research showed that LITAF enhances the activity of the Nav1.5 sodium channel, crucial for heart activity, by increasing its levels and interacting with the ubiquitin ligase NEDD4-2, which normally reduces Nav1.5.
- LITAF overexpression leads to reduced NEDD4-2, increasing Nav1.5 on cell surfaces, and LITAF-knockout zebrafish exhibited changes in heart action potential duration, which aligns with findings from genome-wide studies on QT interval variations.
Article Synopsis
- Enhanced diastolic calcium release from ryanodine receptor type-2 (RyR2) is linked to the development of atrial fibrillation (AF), with ongoing debates about the mechanisms driving changes in RyR2 function.
- The study focused on SPEG, a regulator of RyR2 phosphorylation, by analyzing right atrial biopsies from AF patients and utilizing genetically modified mice.
- Findings revealed lower SPEG levels in AF patients, and SPEG-deficient mice showed increased AF susceptibility and diastolic calcium leak, indicating SPEG's crucial role in the mechanisms underlying AF.
Article Synopsis
- The study aimed to identify genetic variants causing cardiac conduction system disease (CCSD) in patients using whole-exome sequencing (WES) and evaluate the effectiveness of functional studies in determining pathogenicity.
- Researchers conducted WES on 23 patients with early-onset CCSD and analyzed 117 genes associated with heart conditions, identifying five patients with pathogenic protein truncating variants and finding 21 additional variants of uncertain significance.
- Functional analyses using zebrafish models demonstrated that certain genetic variants affected heart function, leading to a reclassification of some variants from uncertain to likely pathogenic in six patients, highlighting the potential of such studies in genetic research.
Background: The turnover of cardiac ion channels underlying action potential duration is regulated by ubiquitination. Genome-wide association studies of QT interval identified several single-nucleotide polymorphisms located in or near genes involved in protein ubiquitination. A genetic variant upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor) gene prompted us to determine its role in modulating cardiac excitation.
View Article and Find Full Text PDFBackground: Abnormal calcium (Ca) release from the sarcoplasmic reticulum (SR) contributes to the pathogenesis of atrial fibrillation (AF). Increased phosphorylation of 2 proteins essential for normal SR-Ca cycling, the type-2 ryanodine receptor (RyR2) and phospholamban (PLN), enhances the susceptibility to AF, but the underlying mechanisms remain unclear. Protein phosphatase 1 (PP1) limits steady-state phosphorylation of both RyR2 and PLN.
View Article and Find Full Text PDFBackground: Heart failure (HF) is a complex disease with a rising prevalence despite advances in treatment. Protein phosphatase 1 (PP1) has long been implicated in HF pathogenesis, but its exact role is both unclear and controversial. Most previous studies measured only the PP1 catalytic subunit (PP1c) without investigating its diverse set of interactors, which confer localization and substrate specificity to the holoenzyme.
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- Duchenne muscular dystrophy patients are susceptible to dangerous heart rhythm issues caused by irregular calcium balance and high levels of reactive oxygen species (ROS).
- The study showed that genetically inhibiting the oxidation of CaMKII, a key protein related to calcium regulation, can prevent these harmful arrhythmias in a mouse model of Duchenne muscular dystrophy.
- Results indicated that this genetic modification not only reduced the occurrence of ventricular tachycardia but also normalized calcium handling in heart cells, proving beneficial against abnormal heart activity.
Rationale: Junctional membrane complexes (JMCs) in myocytes are critical microdomains, in which excitation-contraction coupling occurs. Structural and functional disruption of JMCs underlies contractile dysfunction in failing hearts. However, the role of newly identified JMC protein SPEG (striated muscle preferentially expressed protein kinase) remains unclear.
View Article and Find Full Text PDFReversible phosphorylation of proteins is a delicate yet dynamic balancing act between kinases and phosphatases, the disturbance of which underlies numerous disease processes. While our understanding of protein kinases has grown tremendously over the past decades, relatively little is known regarding protein phosphatases. This may be because protein kinases are great in number and relatively specific in function, and thereby amenable to be studied in isolation, whereas protein phosphatases are much less abundant and more nonspecific in their function.
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- The study investigates the link between heart function and arrhythmias in patients with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), noting that this relationship hasn't been extensively researched before.
- It includes a review of 237 ECG recordings from 91 DMD patients and 64 from 21 BMD patients, with findings showing that arrhythmias are common, affecting 44% of DMD and 57% of BMD patients, and are significantly tied to worsening heart function.
- Clinically significant arrhythmias were observed in 10% of DMD and 25% of BMD patients, and the analysis revealed that arrhythmias increased as heart function declined, with age also
Article Synopsis
- Recent studies challenge the notion that Kv1.1 channels, associated with the Kcna1 gene, are solely neural-specific, revealing their low expression and potential role in heart function and arrhythmogenesis in mice.
- In experiments, Kcna1-null mice showed heightened vulnerability to atrial fibrillation (AF) while displaying minimal remodeling of ion channels and fibrosis, suggesting that Kv1.1 may play an important role in cardiac health.
- Analysis of human atrial tissue from patients with chronic AF showed increased levels of Kv1.1 protein and identified its active involvement in cardiac repolarization and AF pathology, underscoring the channel's significance in heart rhythm disorders.
Background: Cardiac device implantation can be complicated by inability to adequately place leads because of significant lead capture issues. This study sought to determine whether there are genetic bases that underlie poor lead capture.
Methods And Results: Retrospective review of all patients with structurally normal hearts who underwent new device implantation at Texas Children's Hospital between 2009 and 2014 was performed.
Background: The molecular mechanisms underlying the early development of atrial fibrillation (AF) remain poorly understood. Emerging evidence suggests that abnormal epigenetic modulation via microRNAs (miRNAs) might be involved in the pathogenesis of paroxysmal AF (pAF).
Objective: To identify key molecular changes associated with pAF, we conducted state-of-the-art transcriptomic studies to identify the abnormal miRNA-mRNA interactions potentially driving AF development.
Article Synopsis
- * This study aimed to investigate how PP1 regulation is altered in paroxysmal atrial fibrillation (PAF) by examining the interactions between PP1c (the catalytic subunit) and its R-subunits through various techniques like mass spectrometry and coimmunoprecipitation.
- * Results revealed that certain R-subunits, including PPP1R7, CSDA, and PDE5A, showed increased binding to PP1c in PAF patients, indicating that these changes
Background: Enhanced sarcoplasmic reticulum Ca(2+)-leak via ryanodine receptor type-2 (RyR2) contributes to the pathogenesis of atrial fibrillation (AF). Recent studies have shown that the level of RyR2 protein is elevated in atria of patients with paroxysmal AF, suggesting that microRNA-mediated post-transcriptional regulation of RyR2 might be an underlying mechanism. Bioinformatic analysis suggests that miR-106b and miR-93, members of the miR-106b-25 cluster, could bind to RyR2-3'-untranslated region and suppress its translation.
View Article and Find Full Text PDFRationale: Rnd3, a small Rho GTPase, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation. The biological function of Rnd3 in the heart remains unexplored.
Objective: To define the functional role of the Rnd3 gene in the animal heart and investigate the associated molecular mechanism.