Browsing School, Graduate by Subject "KCNMA1-linked channelopathy"
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Evaluation of Motor Function in Mouse Models of KCNMA1-linked ChannelopathyKCNMA1-linked channelopathy is a rare neuromuscular disease associated with patient phenotypes of paroxysmal non-kinesigenic dyskinesia (PNKD). The N999S and D434G variants of the BK channel-encoding KCNMA1 gene currently comprise the largest patient cohorts. Heterologous cellular systems expressing N999S and D434G mutations show gain-of-function property changes, while KO mouse models (Kcnma1–⁄–) show tremors and ataxia associated with increased neuronal excitability of cerebellar Purkinje neurons. Thus, it can be hypothesized that KCNMA1 variants would cause dyskinesia phenotypes in mice. However, there is a lack of evidence in literature suggesting that BK channel property changes from KCNMA1 variants cause PNKD patient phenotypes. In this study, mice harboring N999S (Kcnma1N999S/WT) and D434G (Kcnma1D434G/WT) mutations are exposed to a series of assays evaluating motor function for dyskinesia characteristics. Validation of dyskinesia phenotypes in these mouse models could shape future investigations in molecular mechanisms of genotype-phenotype relations and pharmacologic treatment options.