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.
Vyšlo v časopise: SMA-Causing Missense Mutations in Display a Wide Range of Phenotypes When Modeled in. PLoS Genet 10(8): e32767. doi:10.1371/journal.pgen.1004489 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004489
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