Why on earth two splicing processes? – MIN_SPLICING

RNU4ATAC biallelic variants are responsible for 3 very rare recessive developmental diseases: Taybi-Linder (TALS, or microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1)), Roifman (RFMN) and Lowry-Wood (LWS) syndromes. Beside their common clinical traits (microcephaly, growth retardation, skeletal dysplasia, intellectual deficiency), TALS is slightly more frequent and the most severe, with multiple brain abnormalities and early death. RNU4ATAC is a non-coding gene transcribed into the minor spliceosome component U4atac snRNA, involved in the splicing of 850 minor (or U12) introns located in 700 human genes.
Following our discovery of RNU4ATAC mutations in TALS, we built a comprehensive array of investigations aiming to identify the U12 genes important for embryogenesis and more specifically brain formation, understand the physiopathological and molecular bases of RNU4ATAC-associated diseases, and determine which role minor splicing plays in gene regulation. We perform phenotyping, cellular analysis, neuroimaging, transcriptomics on patients’ cells, as well as knockdown and knock-out zebrafish models, the first animal model known to date for U4atac. Recently, we identified two unrelated RNU4ATAC patients previously suspected of Joubert syndrome, a ciliopathy, suggesting an unexpected link (confirmed in vivo in the zebrafish model) between TALS, minor splicing and the primary cilium. In the future we are going to investigate the underlying mechanisms leading to defects in cerebral development, the part played by cilia in these, and will further caracterize global gene expression dysregulation resulting from minor splicing deficiency. For this purpose, we will expand the range of our biological models by studying human iPSC with specific RNU4ATAC mutations that can be differentiated in neural progenitors and spontaneously form brain organoids, and knock-in zebrafish models to allow long-term expression of mutations.