SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNPs from Cajal bodies to nuclear speckles for spliceosome assembly

Splicing is catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA. We reveal the link between splicing machinery components with the intrinsically disordered ciliopathy protein SANS. Pathogenic mutations in SANS/USH1G lead to Usher syndrome - the most common cause of deaf-blindness. SANS functions has been associated with cytoplasmic processes so far. Here, we show SANS localization in Cajal bodies and nuclear speckles. There SANS interacts with components of spliceosomal complexes and the large splicing cofactor SON and PRPFs of the tri-snRNP complex. SANS is required for the release of tri-snRNPs from Cajal bodies and their recruitment to nuclear speckles. SANS depletion alters spliceosome assembly kinetics, leading to stalled complex A formation, which can be chased to spliced products by the addition of tri-snRNPs. SANS deficiency and USH1G mutations affects splicing of genes related to cell proliferation and USH. We provide the first evidence that splicing deregulation may participate at the pathophysiology of Usher syndrome.