A NOVEL FUNCTION FOR SMN, THE SPINAL MUSCULAR-ATROPHY DISEASE GENE-PRODUCT, IN PRE-MESSENGER-RNA SPLICING

Spinal muscular atrophy (SMA) is a common motor neuron degenerative di sease that results from reduced levels of, or mutations in, the Surviv al of Motor Neurons (SMN) protein. SMN is found in the cytoplasm and t he nucleus where it is concentrated in gems. SMN interacts with splice osomal snRNP proteins and is critical for snRNP assembly in the cytopl asm. We show that a dominant-negative mutant SMN (SMN Delta N27) cause s a dramatic reorganization of snRNPs in the nucleus. Furthermore, SMN Delta N27 inhibits pre-mRNA splicing in vitro, while wild-type SMN st imulates splicing. SMN mutants found in SMA patients cannot stimulate splicing. These findings demonstrate that SMN plays a crucial role in the generation of the pre-mRNA splicing machinery and thus in mRNA bio genesis, and they link the function of SMN in this pathway to SMA.