PMC

Glycosylation of α-dystroglycan. A simplified representation of the post-translational modifications on αDG, with arrows indicating each enzyme's respective glycan additions. POMT1/POMT2 catalyze the first step of glycosylation by adding an O-linked mannose to αDG in a process called O-mannosylation. The LARGE glycosyltransferase catalyzes the final step for the installation of the matriglycan, a repeating disaccharide of variable length that directly binds extracellular laminin. Other enzymes have been shown to be indirectly involved in αDG glycosylation through the synthesis of cytidine diphosphate ribitol (CDP-Rbo) and dolichol phosphate mannose (Dol-P-Man). Pathogenic mutations in each enzyme listed here are linked to the wide clinical spectrum of the α-dystroglycanopathies. For a detailed review, see .

Molecular pathogenesis of α-dystroglycanopathies. (A) Schematic of dystroglycan protein interactions based on biochemical and functional evidence. A truncated form of αDG is most likely on display at the membrane surface, as the N-terminal region is cleaved during Golgi processing (). Matriglycan chains on the central mucin domain of αDG bind directly to laminin in the overlying basement membrane, while βDG is linked to the intracellular actin cytoskeleton through dystrophin. (B) Mutations in glycosyltransferase genes responsible for matriglycan construction cause a hypoglycosylation of αDG, resulting in loss of αDG-laminin binding and disruption of cell-matrix interaction. nNOS, neuronal nitric oxide synthase.

Neural phenotypes in α-dystroglycanopathies. (A) Diagram of the nervous system regions primarily affected in α-dystroglycanopathies. Gross malformations are commonly reported in the brain and eyes and can include displaced neurons and glia (heterotopia), and abnormally small pons and cerebellum (pontocerebellar hypoplasia). These structural phenotypes are often accompanied by functional deficits in cognition and vision (myopia) (; ; ; ). (B) Healthy brain development involves radial migration of newborn neurons (white arrow) into laminae of the cortical plate. Radial glia anchored to the pial basement membrane act as a guiding scaffold. Cortical dysplasia in α-dystroglycanopathy models is characterized by discontinuity of the pial basement membrane, disorganization of radial glial endfeet, abnormal migration of cells into the subarachnoid space and disrupted cortical lamination. CP, cortical plate; GL, glia limitans; IZ, intermediate zone; MZ, marginal zone; PM, pia mater; SAS, subarachnoid space; SP, subplate; VZ, ventricular zone.