sentence stringlengths 10 1.48k | entities listlengths 0 24 | data_source stringclasses 4
values |
|---|---|---|
Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy
Source paper: PMC12256823 | [] | Single_Cell |
POPDC2 encodes the Popeye domain-containing protein 2, which has an important role in cardiac pacemaking and conduction, due in part to its cyclic AMP (cAMP)-dependent binding and regulation of TREK-1 potassium channels. | [] | Single_Cell |
Loss of Popdc2 in mice results in sinus pauses and bradycardia, and morpholino-mediated knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. | [] | Single_Cell |
We identified bi-allelic variants in POPDC2 in four families with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects, and hypertrophic cardiomyopathy. | [] | Single_Cell |
Using homology modeling, we show that the identified variants are predicted to diminish the ability of POPDC2 to bind cAMP. | [] | Single_Cell |
In in vitro electrophysiological studies, we demonstrated that, in contrast with wild-type POPDC2, variants found in affected individuals failed to increase TREK-1 current density. | [] | Single_Cell |
While muscle biopsy of an affected individual did not show clear myopathic disease, it showed significantly reduced abundance of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in either protein. | [
{
"end": 19,
"label": "Cell_Tissue",
"start": 6,
"text": "muscle biopsy"
}
] | Single_Cell |
Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and POPDC2 was most prevalent in AV node, AV node pacemaker, and AV bundle cells. | [
{
"end": 44,
"label": "Cell_Tissue",
"start": 32,
"text": "human hearts"
},
{
"end": 127,
"label": "Cell_Tissue",
"start": 120,
"text": "AV node"
},
{
"end": 146,
"label": "Cell_Tissue",
"start": 129,
"text": "AV node pacemaker"
},
{
"end": 167,
"l... | Single_Cell |
Using population-level genetic data of more than 1 million individuals, we show that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow... | [] | Single_Cell |
Our findings provide evidence for bi-allelic variants in POPDC2 causing a Mendelian autosomal recessive cardiac syndrome. | [] | Single_Cell |
The rhythmic contraction of the heart is orchestrated by the cardiac pacemaker and conduction system. | [
{
"end": 37,
"label": "Cell_Tissue",
"start": 32,
"text": "heart"
}
] | Single_Cell |
Electrical activity in the heart arises in the sinus node, located in the right atrium near the entrance of the superior vena cava. | [
{
"end": 32,
"label": "Cell_Tissue",
"start": 27,
"text": "heart"
},
{
"end": 57,
"label": "Cell_Tissue",
"start": 47,
"text": "sinus node"
},
{
"end": 86,
"label": "Cell_Tissue",
"start": 73,
"text": " right atrium"
},
{
"end": 130,
"label": "Cell... | Single_Cell |
The electrical impulse then spreads through the atria to the atrioventricular (AV) node and is subsequently propagated through the bundle of His and bundle branches to the Purkinje fibers from where it spreads throughout the ventricles. | [
{
"end": 53,
"label": "Cell_Tissue",
"start": 48,
"text": "atria"
},
{
"end": 87,
"label": "Cell_Tissue",
"start": 61,
"text": "atrioventricular (AV) node"
},
{
"end": 144,
"label": "Cell_Tissue",
"start": 131,
"text": "bundle of His"
},
{
"end": 164,
... | Single_Cell |
Cardiac conduction defects (CCDs; MIM: 115080 ) are primarily the consequence of age-related degeneration, structural heart disease, or post-operative complications. | [] | Single_Cell |
Presentation of CCDs in the young should raise suspicion of a genetic disorder. | [] | Single_Cell |
Rare variants in genes encoding cardiac ion channels (e.g., SCN5A , MIM: 600163 ; TRPM4 , MIM: 606936 ; and HCN4 , MIM: 605206 ), transcription factors (e.g., TBX5 , MIM: 601620 ; NKX2-5 , MIM: 600584 ), constituents of the inner nuclear membrane (e.g., LMNA , MIM: 150330 ; EMD , MIM: 300384 ), gap junction proteins (e... | [] | Single_Cell |
602743 ) have been implicated in inherited CCD presenting in isolation or in presence of other cardiac or extracardiac features. | [] | Single_Cell |
However, many affected individuals with early-onset CCD remain genetically unexplained. | [] | Single_Cell |
Bi-allelic variants in POPDC1 (also known as BVES , MIM: 604577 ), encoding the Popeye domain-containing protein 1, are associated with muscular dystrophy and AV block (MIM: 604577 ). | [] | Single_Cell |
In mice, knockout of Popdc1 or Popdc2 resulted in stress-induced sinus pauses and sinus bradycardia. | [] | Single_Cell |
In zebrafish, morpholino knockdown of popdc1 or popdc2 resulted in second-degree AV block and bradycardia. | [] | Single_Cell |
The TWIK-related potassium channel 1 (TREK-1, encoded by KCNK2 ; MIM: 603219 ) is an established interacting protein of POPDC2 (MIM: 605823 ) and co-expression of POPDC2 and TREK-1 has been shown to result in a 2-fold higher TREK-1 current in comparison to expression of TREK-1 alone. | [] | Single_Cell |
Here, we provide evidence for bi-allelic loss-of-function (LOF) variants in POPDC2 as the cause of an autosomal recessive syndrome in four families, consisting of a phenotypic spectrum including sinus node disease and AV conduction defects with hypertrophic cardiomyopathy (HCM; MIM: 192600 ). | [] | Single_Cell |
Family A was referred to the Department of Human Genetics of the Amsterdam UMC (Amsterdam, the Netherlands) for genetic testing and counseling for CCD and HCM. | [] | Single_Cell |
To follow up on the findings from exome sequencing in this family, we studied 78 individuals that were diagnosed with a similar clinical presentation to family A (i.e., CCDs and HCM, cohorts 1–3). | [] | Single_Cell |
In addition, we studied 96 HCM individuals without CCDs (cohort 4). | [] | Single_Cell |
In all 174 individuals, genetic testing had ruled out causative variants in established arrhythmia and/or cardiomyopathy genes. | [] | Single_Cell |
Families C and D were identified via a genetic and phenotypic match through DECIPHER and GeneMatcher, respectively. | [] | Single_Cell |
The study protocol was approved by the Amsterdam University Medical Center Research Ethics Committee and the local Institutional Review Boards of contributing centers. | [] | Single_Cell |
Signed informed consent was obtained from the affected individuals or their parents. | [] | Single_Cell |
Details on case recruitment and DNA-sequencing methods for each family can be found in the supplemental information and Table S1 . | [] | Single_Cell |
To ensure the privacy of the affected individuals and their families, (1) ages are presented as non-overlapping age ranges (i.e., 0–5, 6–10, and 11–15 years), (2) pedigrees were modified, (3) information related to ancestry/country or origin/nationality are not reported, and (4) clinical descriptions were minimized. | [] | Single_Cell |
The censoring undertaken for privacy reasons does not affect the ability to evaluate the presented data. | [] | Single_Cell |
Sex was not considered as a biological variable. | [] | Single_Cell |
Two homology models were generated using either SWISS-MODEL or AlphaFold2 Multimer. | [] | Single_Cell |
The SWISS-MODEL web server used a cyclic AMP (cAMP)-regulatory protein from Yersinia pestis (6DT4) as a template to generate the homology model for the Popeye domain of POPDC2. | [] | Single_Cell |
A dimer of full-length POPDC2 was generated using AlphaFold Multimer, and the intrinsically disordered C-terminal residues 275–364 were deleted to simplify figure presentation. | [] | Single_Cell |
A final homology model of POPDC2 was created by replacing residues 128–213 of the AlphaFold Multimer model with residues 128–213 of the SWISS-cAMP model after superimposing the individual Popeye domains. | [] | Single_Cell |
AlphaMissense was used to generate the predicted pathogenicity of single-amino-acid substitutions and deleted regions. | [] | Single_Cell |
AlphaMissense uses language modeling to understand amino-acid distributions based on sequence context, then it incorporates structural information using an AlphaFold-derived system to consider a protein’s three-dimensional form when assessing a variants’ impact. | [] | Single_Cell |
It also utilizes weak labels from population frequency data to refine predictions without human biases. | [] | Single_Cell |
Using these models, we evaluated the consequence of POPDC2 variants found in families A–D and five variants that occurred homozygously in individuals from the Genome Aggregation Database v2.1.1 (gnomAD), which are not expected to cause disease ( Table S2 )
Source paper: PMC12256823 | [] | Single_Cell |
Single-nucleus RNA-sequencing (snRNA-seq) data and Visium Spatial gene expression data were obtained from a previously published study. | [] | Single_Cell |
Processed data of single-cell RNA-sequencing (scRNA-seq)/snRNA-seq and Visium data are available for browsing gene expression and download from the Heart Cell Atlas ( https://www.heartcellatlas.org ). | [] | Single_Cell |
Annotated, log-normalized count matrices for both modalities were downloaded and specifically analyzed for expression of POPDC1, -2, and -3 using Scanpy package for Python run in Jupyter Notebook. | [] | Single_Cell |
Original histological annotation of tissue sections was used. | [] | Single_Cell |
The cell-state annotation was adapted from the original study. | [] | Single_Cell |
All atrial cardiomyocytes were pooled in one category, and all ventricular cardiomyocytes were pooled together. | [
{
"end": 25,
"label": "Cell_Tissue",
"start": 4,
"text": "atrial cardiomyocytes"
},
{
"end": 89,
"label": "Cell_Tissue",
"start": 63,
"text": "ventricular cardiomyocytes"
}
] | Single_Cell |
From the conduction system cells, sinoatrial node pacemaker (SAN P) cells and Purkinje cells are shown separately; due to low cell numbers, atrioventricular node pacemaker (AVN P) and bundle cells are shown together. | [
{
"end": 32,
"label": "Cell_Tissue",
"start": 9,
"text": "conduction system cells"
},
{
"end": 73,
"label": "Cell_Tissue",
"start": 34,
"text": "sinoatrial node pacemaker (SAN P) cells"
},
{
"end": 92,
"label": "Cell_Tissue",
"start": 78,
"text": "Purkinje cel... | Single_Cell |
Sinus node and AV node/His scRNA-seq data from mice were obtained from a previously published study. | [
{
"end": 10,
"label": "Cell_Tissue",
"start": 0,
"text": "Sinus node"
},
{
"end": 26,
"label": "Cell_Tissue",
"start": 15,
"text": "AV node/His"
}
] | Single_Cell |
Using these data, t-distributed stochastic neighbor embedding (t-SNE) maps with a perplexity of 50 were generated on the R2 environment Genomics Analysis and Visualization Platform ( http://r2.amc.nl ). | [] | Single_Cell |
The cells were subsequently clustered into different populations using the t-SNE DBSCAN tool. | [] | Single_Cell |
Sentinel gene expression was used to characterize the different clusters (e.g., sinus node cells, expressing higher levels of Tbx3 , Isl1 , and Hcn4 ). | [
{
"end": 96,
"label": "Cell_Tissue",
"start": 80,
"text": "sinus node cells"
}
] | Single_Cell |
Thereafter, Popdc1-3 expression intensities were plotted on the t-SNE maps to identify their expression profiles across the present tissue clusters. | [] | Single_Cell |
hTREK-1a cloned in pIRES2-EGFP was obtained from Drs. | [] | Single_Cell |
Delphine Bichet and Florian Lesage (Université Nice Sophia Antipolis, France). | [] | Single_Cell |
Full-length POPDC2 cDNA sequences (NM_001308333-hg19; wild type [WT], c.516_527del: p. | [] | Single_Cell |
Arg263His) were synthesized, cloned into pBluescript IISK+ (GeneCust, Boynes, France), and subsequently subcloned into pIRES-GFP (pCGI). | [] | Single_Cell |
Details on cell preparation and expression can be found in the supplemental information . | [] | Single_Cell |
I Na and TREK-1 currents were measured with ruptured and amphotericin-perforated patch-clamp technique, respectively, using an Axopatch 200B amplifier (Molecular Devices Corporation, Sunnyvale, CA, USA). | [] | Single_Cell |
Voltage control, data acquisition, and analysis were accomplished using custom software. | [] | Single_Cell |
I Na recordings were low-pass filtered with a cutoff frequency of 5 kHz and digitized at 20 kHz, while this was 2 and 4 kHz, respectively, for TREK-1 current measurements. | [] | Single_Cell |
Series resistance was compensated by ≥80%, and potentials were corrected for the calculated liquid junction potential. | [] | Single_Cell |
Cell membrane capacitance (C m ) was calculated by dividing the time constant of the decay of the capacitive transient after a −5-mV voltage step from −40 mV by the series resistance. | [] | Single_Cell |
Patch pipettes were pulled from borosilicate glass (Harvard Apparatus, UK) and had resistances of 2.5–3.5 MΩ after filling with the solutions as indicated below. | [] | Single_Cell |
Measurements from a minimum of nine cells from three independent transfections were acquired for each condition. | [] | Single_Cell |
TREK-1 currents were recorded at 36 ± 0.2°C. | [] | Single_Cell |
Cells were superfused with solution containing (in mM) NaCl 140, KCl 5.4, CaCl 2 1.8, MgCl 2 1, glucose 5.5, and HEPES 5 at pH 7.4 (NaOH). | [] | Single_Cell |
Pipette solution contained (in mM) K-gluc 125, KCl 20, NaCl 5, amphotericin-B 0.88, and HEPES 10 at pH 7.2 (KOH). | [] | Single_Cell |
TREK-1 currents were measured using 500-ms voltage-clamp steps to test potentials ranging from −100 to +50 mV from a holding potential of −80 mV. | [] | Single_Cell |
The TREK-1 current was measured at the end of the voltage-clamp step and current densities were calculated by dividing current amplitude by C m . | [] | Single_Cell |
I Na was measured at room temperature using a bath solution containing (in mM) NaCl 20, CsCl 120, CaCl 2 1.8, MgCl 2 1.0, glucose 5.5, and HEPES 5.0 at pH 7.4 (CsOH). | [] | Single_Cell |
Pipettes were filled with solution containing (in mM) NaF 10, CsCl 10, CsF 110, EGTA 11, CaCl 2 1.0, MgCl 2 1.0, Na 2 ATP 2.0, and 10 HEPES at pH 7.2 (CsOH). | [] | Single_Cell |
The I Na density and voltage dependence of activation were determined by 50-ms depolarizing pulses to test potentials ranging from −80 to +40 mV from a holding potential of −120 mV. Voltage-dependent inactivation was obtained by measuring the peak currents during a 50-ms test step to −20 mV, which followed a 500-ms pre... | [] | Single_Cell |
The holding potential was −120 mV. All voltage-clamp steps were applied with a 5-s cycle length. | [] | Single_Cell |
Peak I Na was defined as the difference between peak and steady-state current. | [] | Single_Cell |
Current density was calculated by dividing the measured currents by C m . | [] | Single_Cell |
To determine the activation characteristics of I Na , current-voltage curves were corrected for differences in driving force and normalized to maximum peak current (I max ). | [] | Single_Cell |
Steady-state activation and inactivation curves were fitted using the Boltzmann equation I/I max = A/ to determine the membrane potential for half-maximal (in)activation (V 1/2 ) and the slope factor k.
Source paper: PMC12256823 | [] | Single_Cell |
Data are presented as mean ± standard error of the mean (SEM). | [] | Single_Cell |
Statistical analysis was carried out with SigmaStat 3.5 software. | [] | Single_Cell |
Normality and equal variance assumptions were tested with the Kolmogorov-Smirnov and the Levene median test, respectively. | [] | Single_Cell |
Groups were compared with one-way ANOVA. | [] | Single_Cell |
p < 0.05 defines statistical significance. | [] | Single_Cell |
The spontaneous electrical activity of a single human sinus nodal pacemaker cell was simulated using the comprehensive mathematical model developed by Fabbri et al. For simulations of a single human atrial cell, we used the model by Maleckar et al. The CellML code of both models, as available from the CellML Model Repo... | [
{
"end": 80,
"label": "Cell_Tissue",
"start": 48,
"text": "human sinus nodal pacemaker cell"
},
{
"end": 210,
"label": "Cell_Tissue",
"start": 193,
"text": "human atrial cell"
}
] | Single_Cell |
TREK-1 currents are not included in both original models. | [] | Single_Cell |
To study whether the homozygous loss LOF variants in POPDC2 contribute to bradycardia via TREK-1 current changes, we fitted our experimental data of the TREK-1 current-voltage relationship ( Figure 3 A) and implemented the thus-obtained TREK-1 current in both models as a control over a range of TREK-1 current densities... | [] | Single_Cell |
Subsequently, the TREK-1 density was reduced to 59% of the TREK-1 + POPDC2-WT current according to the effects induced by the POPDC2 variants ( Figure 3 A) to assess the functional effects of the variants. | [] | Single_Cell |
All simulations were run for a period of 200 s, which appeared a sufficiently long time to reach steady-state behavior. | [] | Single_Cell |
The analyzed data are from the final 10 s of the 200-s period. | [] | Single_Cell |
The recent availability of population-level cohorts with both clinical as well as whole-genome sequencing and well-imputed array genotyping data now provide the opportunity for orthogonal validation of genetic findings through complementary population-level analysis. | [] | Single_Cell |
Samples were included from four large population biobanks (total n = 1,089,031) with genetic data, namely deCODE genetics in Iceland ( n = 173,025), UK Biobank ( n = 428,503), Copenhagen Hospital Biobank and the Danish Blood Donor study in Denmark ( n = 487,356), and Intermountain in Utah, USA ( n = 138,006). | [] | Single_Cell |
Disease status was obtained from electronic health records and ascertained using the following International Classification of Diseases 10th revision codes: atrioventricular block (I44.1 and I44.2), bradycardia (R00.1), cardiac arrest (I46), hypertrophic cardiomyopathy (I42.1 and I42.2), muscular dystrophy (G71.0), myo... | [] | Single_Cell |
Pacemaker implantation was defined based on procedure codes (deCODE: Nomesco Classification of Surgical Procedures [NCSP] codes FPE/FPSE and FPF/FPSF. | [] | Single_Cell |
Copenhagen Hospital Biobank: NCSP codes FPE/FPSE and FPF/FPSF. | [] | Single_Cell |
UK Biobank: National Clinical Coding Standards OPCS code K60). | [] | Single_Cell |
Heart rate was available only in the UK Biobank and deCODE. | [] | Single_Cell |
In the UK Biobank, heart rate was obtained during blood-pressure measurement at assessment. | [] | Single_Cell |
Both measurements were taken twice, and multiple measurements for one individual were averaged. | [] | Single_Cell |
In deCODE, heart-rate measurements were sourced from electrocardiograms (ECGs) from Landspitali University Hospital in Iceland between 1998 and 2015. | [] | Single_Cell |
End of preview. Expand in Data Studio
README.md exists but content is empty.
- Downloads last month
- 25