SMN mutants of spinal muscular atrophy patients are defective in binding to snRNP proteins

Spinal muscular atrophy (SMA) is a common motor neuron degenerative disease and the leading genetic cause of death of young children. The survival of motor neurons (SMN) gene, the SMA disease gene, is homozygously deleted or mutated in more than 98% of SMA patients. The SMN protein interacts with it self, with SMN-interacting protein 1, and with several spliceosomal small n uclear ribonucleoprotein (snRNP) Sm proteins. A complex containing SMN play s a critical role in spliceosomal snRNP assembly and in pre-mRNA splicing. SMN mutants found in SMA patients show reduced self association and lack th e capacity to regenerate the splicing machinery. Here we demonstrate that S MN mutants found in SMA patients are defective in binding to Sm proteins. M oreover, we show that SMN, but not mutants found in SMA patients, can form large oligomers and that SMN oligomerization is required for high-affinity binding to spliceosomal snRNP Sm proteins. These findings directly link the impaired interaction between SMN and Sm proteins to a defect in snRNP meta bolism and to SMA.