RPTPζ/phosphacan is abnormally glycosylated in a model of muscle-eye-brain disease lacking functional POMGnT1.

Congenital muscular dystrophies (CMDs) with associated brain abnormalities are a group of disorders characterized by muscular dystrophy and brain and eye abnormalities that are frequently caused by mutations in known or putative glycotransferases involved in protein O-mannosyl glycosylation. Previous work identified α-dystroglycan as the major substrate for O-mannosylation and its altered glycosylation the major cause of these disorders. However, work from several labs indicated that other proteins in the brain are also O-mannosylated and therefore could contribute to CMD pathology in patients with mutations in the protein O-mannosylation pathway, however few of these proteins have been identified and fully characterized in CMDs. In this study we identify receptor protein tyrosine phosphatase ζ (RPTPζ) and its secreted variant, phosphacan, as another potentially important substrate for protein O-mannosylation in the brain. Using a mouse model of muscle-eye-brain disease lacking functional protein O-mannose β-1,2-N-acetylglucosaminyltransferase (POMGnT1), we show that RPTPζ/phosphacan is shifted to a lower molecular weight and distinct carbohydrate epitopes normally detected on the protein are either absent or substantially reduced, including Human Natural Killer-1 (HNK-1) reactivity. The spatial and temporal expression patterns of these O-mannosylated forms of RPTPζ/phosphacan and its hypoglycosylation and loss of HNK-1 glycan epitopes in POMGnT1 knockouts are suggestive of a role in the neural phenotypes observed in patients and animal models of CMDs.