SMN Mutants of Spinal Muscular Atrophy Patients Are Defective in Binding to snRNP Proteins

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 20; pp. 11167 - 11172
• Main Authors: Pellizzoni, L, Charroux, B, Dreyfuss, G
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 28.09.1999; National Acad Sciences; The National Academy of Sciences
• Subjects: Antibodies; Autoantigens - chemistry; Autoantigens - genetics; Autoantigens - metabolism; Binding sites; Biological Sciences; Cells, Cultured; Goods and services tax; Humans; Motor neuron disease; Motor neurons; Muscular Atrophy, Spinal - genetics; Mutation; Nervous system diseases; Oligomers; Ribonucleoproteins, Small Nuclear - metabolism; Small nuclear ribonucleoproteins; snRNP Core Proteins; Teeth; Western blotting
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.20.11167

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 itself, with SMN-interacting protein 1, and with several spliceosomal small nuclear ribonucleoprotein (snRNP) Sm proteins. A complex containing SMN plays a critical role in spliceosomal snRNP assembly and in pre-mRNA splicing. SMN mutants found in SMA patients show reduced self-association and lack the capacity to regenerate the splicing machinery. Here we demonstrate that SMN mutants found in SMA patients are defective in binding to Sm proteins. Moreover, 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 metabolism and to SMA.