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 links 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 have been associated with cytoplasmic processes so far. Here, we reveal molecular links between SANS and pre-mRNA splicing catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA in the nucleus. Here, we show SANS associates with Cajal bodies and nuclear speckles, where SANS interacts with components of spliceosomal sub-complexes such as SF3B1 and the large splicing cofactor SON but also with PRPFs and snRNAs related to the tri-snRNP complex. SANS is required for the transfer of tri-snRNPs from Cajal bodies to nuclear speckles. SANS depletion alters the kinetics of spliceosome assembly, leading to accumulation of Complex A. SANS deficiency and USH1G pathogenic mutations affects splicing of genes related to cell proliferation and USH. Thus, we provide the first evidence that splicing deregulation may participate in the pathophysiology of Usher syndrome.