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dc.contributor.authorLiu, Liu
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 67-06, Section: B, page: 2944.;Advisors: Laurie J. Ozelius.
dc.description.abstractMyoclonus-dystonia syndrome (M-D) has been defined as an autosomal dominant disorder characterized by myoclonic jerks and dystonia that are often responsive to alcohol. In the majority of families, the disease has been linked to chromosome 7q21. Loss of function mutations in the gene epsilon-sarcoglycan (SGCE) were reported to cause the disease. One affected member from each M-D families was selected and screened for mutations within SGCE using denaturing high performance liquid chromatography (DHPLC) and direct sequencing. Quantitative PCR was performed in patients with a classic M-D phenotype in whom we failed to detect point mutations in the previous mutation screen. In total we identified 33 point mutations or small deletions/insertions and 6 genomic deletions around the SGCE gene locus. These findings confirmed the causative nature of the SGCE gene in M-D disease.;In order to characterize the functionality of several missense mutations identified in M-D patients, we generated C-terminus myc-tagged wildtype (wt) and mutant constructs in the mammalian expression vector pCAGGS. Using these vectors, our immunofluroscence experiments revealed that wt C-terminal myc-tagged protein was mainly localized to the plasma membrane while most mutant constructs were found trapped in the cytoplasm, primarily co-localized with an endoplasmic reticulum (ER) resident protein, Protein Disulfide Isomerase (PDI). However, one mutation located in the transmembrane domain of SGCE, P324R, co-localized with the wt SGCE protein at the plasma membrane. SGCE is known to be part of the dystrophin-glycoprotein complex in muscles and to bind to other sarcoglycan family members. Co-IP experiments revealed that only mutant P324R, the missense mutation that was correctly targeted to the cell surface, lost the ability to associate with the sarcoglycan complex. Through the study of SGCE missense mutations originally identified in M-D patient, we showed that most of these mutations cause intracellular accumulation of the mutant protein mainly in the ER while the one mutant protein that appears to be localized to the plasma membrane, shows dissociation from the sarcoglycan complex. These findings will help better interpret the M-D disease.
dc.publisherProQuest Dissertations & Theses
dc.titleSGCE mutations and myoclonus -dystonia disease

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