The mammalian O‐mannosylation pathway: protein substrates, enzymes, and structures

The O‐linked mannose modification imparts essential functions to targeted glycoproteins. The protein substrates, enzymes, and glycan products of the O‐mannosylation pathway underlie a variety of cellular processes and their perturbation contribute to diverse pathophysiological conditions including congenital muscular dystrophy, viral‐host interactions, and tumor metastasis. We are currently identifying the protein substrates and sites of modification for O‐mannosylation in mammalian brain and muscle using chemical biology approaches coupled to novel tandem mass spectrometry approaches. We are also developing genotype/phenotype correlations for POMGnT1 that when mutated can generate phenotypes ranging from Muscle‐Eye‐Brain disease to the much less severe limb‐girdle muscular dystrophy. Also, we have recently established the presence of O‐mannose structures on leukocytes and have demonstrated that we can use a mass spectrometry‐based blood test to differentiate between controls and patients with Walker‐Warburg syndrome, the most severe of the congenital muscular dystrophies. Finally, using analytical biochemical methods, we are attempting to determine the complete O‐mannose‐initiated structure(s) and the enzymes responsible for synthesis that are used for binding components of the extracellular matrix.