Modeling human spinal muscular atrophy mutations in Drosophila melanogaster Public Deposited

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  • March 22, 2019
  • Praveen, Kavita
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
  • Spinal Muscular Atrophy (SMA) is a common neuromuscular disease that affects one in 6,000-8,000 young children; most of whom die before reaching the age of two years. One in fifty Americans is a carrier for SMA, making this genetic disease a serious health concern. More than 95% of patients with SMA carry deletions in the survival motor neuron 1 (SMN1) gene. The SMN protein is essential for survival and has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), which are core components of the spliceosome. Numerous additional functions, both housekeeping and tissue-specific, have been put forth in the literature, however, no convincing link has been made between any putative SMN function and the disease etiology. To address this question, we are studying the consequences of SMN loss in the Drosophila model system. We have generated a series of transgenic flies that exclusively express mutant forms of SMN derived from human SMA patients to uncouple the housekeeping and tissue-specific functions of SMN. Null mutants in Smn die as larvae, show significant motility defects, and have reduced levels of minor-class snRNAs. Surprisingly, despite these reductions, minor-class intron splicing in these mutants is unperturbed. In addition, we find that rescue of the null mutant with a WT SMN construct does not restore snRNA levels, but does rescue the motility defects and lethality of the Smn null flies. In addition, the majority of flies expressing an SMA point mutation, T205I, die as pupae but have a similar snRNA profile to the WT transgenic animals. These data suggest that the reduction in snRNAs in Smn mutants is not a major contributor to their lethality, and indicate that non-snRNP related functions of SMN may be critical to SMA pathology. We have generated twelve additional point mutations in Smn that mimic mutations identified in SMA patients. The phenotypes of these mutations reflect the range of severities seen in SMA patients, and will be important tools in identifying the functions of SMN that form the etiological basis for SMA.
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  • Matera, Gregory
  • Doctor of Philosophy
Graduation year
  • 2012

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