Establishing genotype-phenotype relationships in POMGnT1 associated with congenital muscular dystrophy
Stuart, Ryan Patrick
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Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase1 (POMGnT1) is an influential glycosyltransferase required for modifying α-dystroglycan. Mutations in POMGnT1, removing GlcNAc modifications, have been associated with muscle-eye-brain (MEB) disease, a congenital muscular dystrophy. There are a number of varying phenotypes associated with MEB disease, corresponding to different point mutations in POMGnT1. In this study specific point mutations of POMGnT1 were selected to be examined, such that phenotype-genotype relationship can begin to be established. Using mass spectrometry and radiolabeled UDP-GlcNAc we were able to confirm that rPOMGnT1 was catalytically active. Through our analysis, we were able to compare the maximum initial velocity of the mutants as well as their thermal stability. Additionally, through homology modeling, predicted changes in tertiary structures could be associated with a loss of function. This data suggest that there could be a correlation between POMGnT1 expression and efficiency and disease phenotype.