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Multiple mechanisms lead to differential loss-of-function effects of pathogenic SARS2 variants: implications for genotype-phenotype analyses II

GSE329548 Homo sapiens (human) RNA-seq (gene expression) 9 samples Submitted 2026/06/29 Platform GPL34284
At a glance

RNA-seq (gene expression) · human · 9 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
Homo sapiens (human)
Samples
9 samples: 3 × ∆SARS2+SARS2-1xFLAG Hap1 Cells + WT SARS2+int14-myc grown without dox vs 3 × ∆SARS2+SARS2-1xFLAG Hap1 Cells + R227Q SARS2+int14-myc grown without dox vs 3 × ∆SARS2+SARS2-1xFLAG Hap1 Cells + H448L SARS2+int14-myc grown without doxGroups 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)
Seryl-tRNA synthetase 2 (SARS2) encodes the enzyme responsible for charging tRNA with serine in the mitochondria. SARS2 has been associated with a spectrum of recessive diseases including HUPRA syndrome and progressive spastic paresis (PSP). Previous studies showed that pathogenic SARS2 variants cause decreased tRNA charging; however, the mechanism by which specific variants lead to distinct recessive phenotypes has not been defined.
Read the full summary ↓
To address this lack of knowledge, we studied an allelic series of pathogenic SARS2 variants for differential effects on mitochondrial function. We generated a SARS2 knockout Hap1 cell line with a second, doxycycline-inducible wild-type copy of SARS2 to support cell growth. We first assessed the effects of ablated SARS2 expression on the transcriptome and on mitochondrial function. We found that, in the absence of SARS2 expression, transcriptional changes indicate activation of cellular stress responses including the integrated stress response. Furthermore, loss of SARS2 resulted in severely depleted oxygen consumption in Seahorse assays. We next individually transduced an allelic series of 11 pathogenic SARS2 variants into this cell model to assess the effects of each variant on mitochondrial function. These efforts revealed compelling variant-dependent effects on oxygen consumption that will be useful for phenotype-genotype correlations. Interestingly, the most commonly detected pathogenic SARS2 variant (R402H) had no effect on mitochondrial function in our model system. We performed computational and functional studies, which showed that this missense variant has a partial effect on exon inclusion, which predicts a hypomorphic allele consistent with certain patients being reported as homozygous for this variant. Overall, this study expands our understanding of SARS2 biology, reveals the differential effects that pathogenic variants have on SARS2 function, and provides the foundation for defining the clinical heterogeneity of patient phenotypes.
This dataset
Open GSE329548 in finder → Find more human 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 GSE329548_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 PRJNA1459488 and SRA study SRP696104. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗
Study design
3 × ∆SARS2+SARS2-1xFLAG Hap1 Cells + WT SARS2+int14-myc grown without dox vs 3 × ∆SARS2+SARS2-1xFLAG Hap1 Cells + R227Q SARS2+int14-myc grown without dox vs 3 × ∆SARS2+SARS2-1xFLAG Hap1 Cells + H448L SARS2+int14-myc grown without dox

Supports a between-group comparison across 9 samples.

How we read this: 3 replicated groups read from 9 sample titles; they account for 9 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
Datasets on a similar topic

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