Modeling Spinal Muscular Atrophy point mutations in Drosophila melanogaster. A Gregory Matera, Kavita Praveen, Ying Wen. Department of Biology, Univ of North Carolina, Chapel Hill, NC.

   Spinal Muscular Atrophy (SMA) is a prevalent childhood neuromuscular disease. In its most common form, SMA causes death by the age of two years. The disease 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 role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), which are core components of the spliceosome. Numerous additional functions for SMN have been put forth in the literature, however, no convincing link has been made between any putative SMN function and the disease etiology. We have studied the consequences of SMN loss in the Drosophila model system by generating a series of transgenic flies that exclusively express mutant forms of SMN that mimic mutations identified in human SMA patients. Null mutants in Smn die as larvae, have significant locomotor defects and reduced levels of minor-class snRNAs. Surprisingly, despite these reductions, minor-class intron splicing in Smn null mutants is unperturbed. In addition, transgenic expression of low levels of a wild-type or an SMA patient-derived mutant dSMN rescued the larval lethality and locomotor defects, however, snRNA levels were not restored. These data provide genetic evidence that non-snRNP related functions of SMN may be critical to SMA pathology. We have also generated flies carrying twelve additional SMA patient-derived Smn point mutations. These mutants vary in severity, recapitulating the full range of severity observed in humans. We are currently using these animals for RNA-seq and proteomic analyses to understand the differential effects of these mutations. These new SMA models will be important tools in identifying functions of SMN that are etiologic for SMA.