A faulty molecular machine called the minor spliceosome is cutting genetic messages incorrectly in people with severe growth disorders and tissue damage. This matters because errors in RNA splicing—the process that edits gene transcripts before they become proteins—are linked to cancers, immune deficiencies, and neurological diseases. But scientists do not understand exactly how these errors cause disease. The researcher has created mouse cells and whole mice carrying a mutation found in patients with a rare disease called U4atac deficiency, which causes severe growth problems and tissue-specific defects. By tracking which tissues are affected during embryonic development and analysing which genes are mis-spliced, the work will reveal whether minor splicing errors specifically disrupt cell division, chromosome segregation, or genome stability. This is fundamental science. It will not produce a treatment or diagnostic test in the short term. But understanding how a single faulty RNA molecule can cause different problems in different tissues could eventually explain why splicing defects appear in common conditions such as leukaemia and early-onset ataxia. Similar fundamental work on RNA processing has previously uncovered the mechanisms behind spinal muscular atrophy and certain forms of inherited blindness.
View original technical description
Defects in RNA splicing are associated with human diseases including cancer, immunodeficiency and neurological degeneration. However, understanding the mechanisms underlying these associations is challenging. Monogenic diseases of splicing genes offer an opportunity to address this question. Here, I aim to understand the pathophysiological consequences of defects in minor splicing, a conserved pathway responsible for removing minor introns from about 700 human transcripts. Biallelic mutations in U4atac, a non-coding RNA of the minor spliceosome, result in severe growth impairment and tissue-specific defects. I hypothesise that minor splicing has a particular role in regulating the cell cycle, and that disease-linked mutations impair cell proliferation. To test this, I have generated mouse cell lines carrying disease-associated U4atac mutations. I will examine whether the cell cycle is dysregulated in these cells, and whether this is related to chromosome segregation or genome stability defects. A major research question is whether impaired minor splicing affects specific spatiotemporal locations during embryogenesis. To investigate this, I have created a mouse model with a disease-linked U4atac mutation. I will use RNASeq and flow cytometry to identify affected tissues and time points in homozygous embryos, and analyse the transcriptome to identify potential disease-relevant mis-spliced mRNA species. These studies will lay the foundation for future research investigating tissue-specific aspects of the U4atac disease spectrum, such as adaptive immune deficiency. They will also inform future studies investigating minor splicing defects in diseases such as acquired blood dyscrasias and early-onset cerebellar ataxia, as well broader questions related to RNA processing in human disease.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know