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dc.contributor.advisorLorson, Christian (Christian Lawrence), 1969-eng
dc.contributor.authorMattis, Virginia B., 1982-eng
dc.date.issued2009eng
dc.date.submitted2009 Springeng
dc.descriptionThe entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.eng
dc.descriptionVita.eng
dc.description"May 2009"eng
dc.descriptionThesis (Ph. D.) University of Missouri-Columbia 2009.eng
dc.description.abstract[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Spinal Muscular Atrophy is an autosomal recessive neuromuscular disorder that is the leading genetic cause of infant mortality. In humans, a nearly identical copy gene is present called SMN2 that is retained in all SMA patients and encodes an identical protein compared to SMN1. However, SMN1 and SMN2 differ by a silent C to T transition at the 5' end of exon 7. This single nucleotide difference results in the production of an alternatively spliced isoform, called SMN[delta]7, which encodes an unstable and non-functional protein. Therefore, the absence of the short peptide encoded by SMN exon 7 is critical in the disease development process. A cytoplasmic localization signal has been previously identified within SMN exon 7 and can readily transport SMN and heterologous proteins to the cytoplasm. While this peptide is important for SMN protein function, here it is shown heterologous sequences can seemingly compensate for the SMN exon 7 peptide, regarding: SMN protein localization, protein stability, supporting neurite outgrowth, and snRNP assembly. Consistent with this, aminoglycosides that suppress efficient recognition of stop codons, known as "read-through" (Rt), resulted in significantly increased levels of SMN protein in SMA patient fibroblasts. It is also shown in this work these aminoglycosides increase lifespan and gross-motor function in SMA model mice. Collectively, these experiments help to provide insight into therapeutics designed to induce readthrough of the SMN[delta]7 stop codon, as well as other routes of therapeutic intervention to be used in combination with a read-through event.eng
dc.description.bibrefIncludes bibliographical references.eng
dc.identifier.merlinb70559107eng
dc.identifier.oclc427372716eng
dc.identifier.urihttps://hdl.handle.net/10355/6761
dc.identifier.urihttps://doi.org/10.32469/10355/6761eng
dc.languageEnglisheng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartofcommunityUniversity of Missouri--Columbia. Graduate School. Theses and Dissertationseng
dc.rightsAccess is limited to the campus of the University of Missouri--Columbia.eng
dc.subject.lcshSpinal muscular atrophy -- Genetic aspectseng
dc.subject.lcshRNA-protein interactionseng
dc.titleMolecular genetics of spinal muscular atrophy : insights into various routes of therapeutic interventioneng
dc.typeThesiseng
thesis.degree.disciplineVeterinary pathobiology (MU)eng
thesis.degree.grantorUniversity of Missouri--Columbiaeng
thesis.degree.levelDoctoraleng
thesis.degree.namePh. D.eng


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