Cell-type-specific alternative splicing in the cerebral cortex of a Schinzel-Giedion Syndrome patient variant mouse model

Abstract

AbstractSchinzel-Giedion Syndrome (SGS) is an ultra-rare Mendelian disorder caused by gain-of-function mutations in theSETBP1gene. While previous studies determined multiple roles for howSETBP1and associated pathways may cause disease manifestation, they have not assessed whether cell-type-specific alternative splicing (AS) plays a role in SGS. We used STARsolo to quantify gene and splice junction (SJ) expression for 51,465 nuclei previously generated from the cerebral cortex of atypicalSetbp1S858RSGS patient variant mice (n = 3) and wild-type control mice (n = 3). After cell type annotation, we performed pseudobulk differential gene expression and SJ usage (SJU) analyses across cell types and conditions. We identified 34 genes with statistically significant alterations in SJU. Oligodendrocytes had the most genes with changes in SJU, followed by astrocytes, excitatory, and inhibitory neurons. One gene,Son, a splicing cofactor known to cause the neurodevelopmental disorder ZTTK Syndrome, had SJU changes in all six non-vascular cell types we measured inSetbp1S858Rcompared to controls. This is the first research to report AS changes in the cerebral cortex of an SGS model and the first study to link SGS to perturbations inSon.