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Compound mutations in HRC and MYBPC3 synergistically increase cardiac pathogenicity

GSE279737 Mus musculus (mouse) RNA-seq (gene expression) 12 samples Submitted 2024/10/24 Platform GPL23479
At a glance

RNA-seq (gene expression) · mouse · 12 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Mus musculus (mouse)
Samples
12 samples: 3 × Non transgenic vs 3 × MYBPC3Δ25bp homozygous vs 3 × HRCS96A mutant heterozygous vs 3 × HRCS96A Het+MYBPC3Δ25bp HomGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Summary (written by the submitters)
Hypertrophic cardiomyopathy (HCM) and arrhythmia are two leading causes of sudden cardiac death (SCD). A 25-base pair deletion in intron 32 of cardiac myosin binding protein C (MYBPC3Δ25bp) results in cardiomyopathies in 6% of South Asians. Within this population, another compounded genetic variant of a Serine to Alanine mutation in the 96th codon of HRC (HRCS96A) is present with frequencies of 48% (heterozygous) and ~16% (homozygous), resulting in a higher incidence of sudden death in dilated cardiomyopathy (DCM).
Read the full summary ↓
To elucidate the pathogenicity of impaired Ca2+-cycling and arrhythmias by the HRCS96A polymorphism in the setting of altered sarcomere function instrumented by the MYBPC3Δ25bp variant. Using transgenic mouse models, we studied the effects of the MYBPC3Δ25bp and the HRC mutation (murine S81A) alone and together (double variant, DV). Electrocardiogram tracing of DV mice also indicated increased stress-induced arrhythmias, such as ventricular tachycardia, after caffeine and epinephrine administration. In vitro, IonOptix experiments using freshly isolated adult cardiomyocytes revealed DV mice significantly decreased fractional shortening, Ca2+ transient amplitude, and higher number of after-contraction. When challenged with transverse aortic constriction (TAC), the DV mice also displayed more severe systolic and diastolic dysfunction as measured by echocardiography. In subsequent RNA sequencing studies, compared to the non-transgenic controls, the DV mice had significantly more dysregulated genes than the single-variant mice. A perturbagen screen followed the RNA sequencing study to predict small molecules could revert these pathological gene signatures in the DV mice. These studies highlight the increased pathogenicity of compound variants in calcium handling and sarcomeric genes, as evidenced by increased cardiac dysfunction at baseline and post-TAC and increased pathological gene dysregulation in the double variant mice.
This dataset
Open GSE279737 in finder → Find more mouse RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE279737_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1174185 and SRA study SRP539190. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗
Study design
3 × Non transgenic vs 3 × MYBPC3Δ25bp homozygous vs 3 × HRCS96A mutant heterozygous vs 3 × HRCS96A Het+MYBPC3Δ25bp Hom

Supports a between-group comparison across 12 samples.

How we read this: 4 replicated groups read from 12 sample titles; they account for 12 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
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