Cell-type-specific alternative splicing in the brain and kidney of a Setbp1^S858R Schinzel-Giedion syndrome mouse

2026-02-27

Publication:

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Authors

Tabea M. Soelter^#, Emma F. Jones^#, Timothy C. Howton, Anthony B. Crumley, Elizabeth J. Wilk, Brittany N. Lasseigne*

#Equal contribution
*Corresponding author

Project Overview

Schinzel-Giedion syndrome (SGS) is an ultra-rare Mendelian disorder caused by gain-of-function variants in the SETBP1 gene. Although previous studies determined multiple roles for SETBP1 and its associated pathways in disease manifestation, they did not assess whether cell-type-specific alternative splicing (AS) plays a role in SGS. We quantified gene and splice junction expression from single-nuclei RNA-sequencing data from the cerebral cortex and the kidney of atypical Setbp1^S858R SGS patient variant and wild-type mice. We identified 33 and 62 genes with statistically significant alterations in splice junction usage in the brain and the kidney, respectively. We identified significant splice junction usage in a member of the heterogeneous nuclear ribonucleoprotein family, Hnrnpa2b1. These findings were cell-type-specific in the cerebral cortex and cell-type-agnostic in the kidney, suggesting tissue-specificity of AS in Setbp1^S858R mice. To broaden the impact of our results for the rare disease community, we developed a point-and-click web application that enables users to explore single-cell-resolution changes at the gene and splice junction levels. Overall, our findings implicate AS in a tissue- and cell-type-specific manner in the cerebral cortex and kidney of Setbp1^S858R mice.

Scripts

## src
## ├── README
## ├── ambientRNA-removal
## │   ├── 01_ambientRNA_removal.R
## │   └── 01_ambientRNA_removal.sh
## ├── deseq2
## │   ├── 01_pseudobulk_analysis.Rmd
## │   ├── 02_pseudobulk_analysis_kidney.R
## │   ├── 02_pseudobulk_analysis_kidney.sh
## │   └── functions.R
## ├── figures
## │   ├── figure_2.Rmd
## │   ├── figure_3-4.Rmd
## │   ├── figure_5.Rmd
## │   ├── functions.R
## │   ├── geom_split_violin.R
## │   ├── kidney_marvel_figures.R
## │   ├── kidney_marvel_figures.sh
## │   ├── kidney_overview_figure.R
## │   ├── kidney_overview_figure.sh
## │   ├── mean_expression_celltype.R
## │   └── supp_figure_2.Rmd
## ├── functions_soelter.R
## ├── marvel
## │   ├── 01_format_MARVEL_data.Rmd
## │   ├── 02_MARVEL_differential_analysis.Rmd
## │   ├── 03_analyze_de_genes.Rmd
## │   ├── 04_calc_sj_usage.Rmd
## │   ├── 05_cell_specific_sj_expr.Rmd
## │   ├── 06_format_kidney_MARVEL_data.R
## │   ├── 06_format_kidney_MARVEL_data.sh
## │   ├── 07_kidney_MARVEL_differential_analysis.R
## │   ├── 07_kidney_MARVEL_differential_analysis.sh
## │   ├── 08_analyze_kidney_de_genes.R
## │   ├── 08_analyze_kidney_de_genes.sh
## │   ├── 09_calc_sj_usage_kidney.R
## │   ├── 09_calc_sj_usage_kidney.sh
## │   ├── 10_cell_specific_kidney_sj_expr.R
## │   ├── 10_cell_specific_kidney_sj_expr.sh
## │   ├── PlotSJPosition_modification.R
## │   └── functions.R
## ├── samtools
## │   └── sort_index_bam.sh
## ├── seurat
## │   ├── 01_import_filter_data.Rmd
## │   ├── 02_annotate_cell_types.Rmd
## │   ├── 03_kidney_preprocessing.R
## │   ├── 03_kidney_preprocessing.sh
## │   ├── functions.R
## │   └── generate_cellcycle_lists.R
## └── starsolo_conda
##     ├── 01_build_STAR_genome.sh
##     ├── 02_run_STARsolo.sh
##     └── README

Lasseigne Lab

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Funding

This work was funded by the UAB Lasseigne Lab funds and the UAB Pilot Center for Precision Animal Modeling (C-PAM) (1U54OD030167).

Acknowledgements

We would like to acknowledge all current and former members of the Lasseigne Lab for their thoughtful feedback, especially Amanda D. Clark and Vishal H. Oza. The graphical abstract was created using BioRender.

License

This repository is licensed under the MIT License, see LICENSE documentation within this repository for more details.