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Sci Rep 2019 Jul 01;91:9472. doi: 10.1038/s41598-019-45822-8.
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Functional characterization of SMN evolution in mouse models of SMA.

Osman EY , Bolding MR , Villalón E , Kaifer KA , Lorson ZC , Tisdale S , Hao Y , Conant GC , Pires JC , Pellizzoni L , Lorson CL .

Spinal Muscular Atrophy (SMA) is a monogenic neurodegenerative disorder and the leading genetic cause of infantile mortality. While several functions have been ascribed to the SMN (survival motor neuron) protein, their specific contribution to the disease has yet to be fully elucidated. We hypothesized that some, but not all, SMN homologues would rescue the SMA phenotype in mouse models, thereby identifying disease-relevant domains. Using AAV9 to deliver Smn homologs to SMA mice, we identified a conservation threshold that marks the boundary at which homologs can rescue the SMA phenotype. Smn from Danio rerio and Xenopus laevis significantly prevent disease, whereas Smn from Drosophila melanogaster, Caenorhabditis elegans, and Schizosaccharomyces pombe was significantly less efficacious. This phenotypic rescue correlated with correction of RNA processing defects induced by SMN deficiency and neuromuscular junction pathology. Based upon the sequence conservation in the rescuing homologs, a minimal SMN construct was designed consisting of exons 2, 3, and 6, which showed a partial rescue of the SMA phenotype. While a significant extension in survival was observed, the absence of a complete rescue suggests that while the core conserved region is essential, additional sequences contribute to the overall ability of the SMN protein to rescue disease pathology.

PubMed ID: 31263170
PMC ID: PMC6603021
Article link: Sci Rep
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: smn1

Disease Ontology terms: spinal muscular atrophy

Article Images: [+] show captions
References [+] :
Bertrandy, The RNA-binding properties of SMN: deletion analysis of the zebrafish orthologue defines domains conserved in evolution. 1999, Pubmed