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Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.

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Spinal Muscular Atrophy (SMA) is a prevalent childhood neuromuscular disease, which in its most common form causes death by the age of two. One in fifty Americans is a carrier for SMA, making this genetic disease a serious health concern. SMA is caused by loss of function mutations in the survival motor neuron 1 (SMN1) gene. SMN is an essential protein and has a well-characterized function in the assembly of small nuclear ribonucleoproteins (snRNPs), which are core components of the spliceosome. To elucidate the phenotypic consequences of disrupting specific SMN protein interactions, we have generated a series of SMA-causing point mutations, modeled in Drosophila melanogaster. Using this system, we have shown that key aspects of SMN structure and function are conserved between humans and flies. Intragenic complementation analyses reveal the potential for dominant negative interactions between wild-type and mutant SMN subunits, highlighting the essential nature of the YG box in formation of higher-order SMN multimers. These results provide a basis for future studies investigating therapy targeted at restoration of functional SMN oligomers.


This article was originally published in PLoS Genetics, volume 10, issue 8, in 2014.


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