Meta-Biol

• Pathways

Three enzymes are involved in the biosynthesis of a phosphorylated O-mannosyl trisaccharide structure (N-acetylgalactosamine-beta-1,3-N-acetylglucosamine-beta-1,4-(phosphate-6-)mannose) present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity. Defects in any of these enzymes can lead to congenital muscular dystrophy.

In the first step, protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2) transfers N-acetyl-D-glucosamine (GlcNAc) to the 4-position of mannosylated DAG1 to generate N-acetyl-D-glucosamine-beta-1,4-O-D-mannosyl-DAG1 (Yoshida-Moriguchi et al. 2013). Defects in POMGNT2 can cause muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A8 (MDDGA8), a congenital muscular dystrophy that severely affects the development of the brain, eyes, and muscle, profound mental retardation, and death usually in the first years of life. This phenotype is also described as Walker-Warburg syndrome (WWS), which represents the most severe end of a phenotypic spectrum of dystroglycanopathies (Manzini et al. 2012).