Dissecting the Molecular Basis of the Role of the O‐Mannosylation Pathway in Disease: α‐Dystroglycan and Forms of Muscular Dystrophy

Abstract

Dystroglycanopathies are a subgroup of muscular dystrophies that arise from defects in the enzymes implicated in the recently elucidated O-mannosylation pathway, resulting in underglycosylation of α-dystroglycan. The emerging identification of additional brain proteins modified by O-mannosylation provides a broader context for interpreting the range of neurological consequences associated with dystroglycanopathies. This form of glycosylation is associated with protein mucin-like domains which present numerous serine and threonine residues as possible sites for modification. Further, the O-Man glycans coexist in this region with O-GalNAc glycans, conventionally associated with such protein sequences, resulting in a complex glycoconjugate landscape. Sorting out the relationships between the various molecular defects in glycosylation and the modes of disease presentation, as well as the regulatory interplay among the O-Man glycans, and the effects on other modes of glycosylation in the same domain is challenging. Here we provide a perspective on chemical biology approaches employing synthetic and analytical methods to address these questions.

Intrafamilial variability in GMPPB -associated dystroglycanopathy: Broadening of the phenotype

“…Many of the aDG-RD genes encode glycosyltransferases that add O-linked mannose to aDG or contribute to the synthesis of the final LARGE-dependent glycan that binds to extracellular matrix ligands or are kinases or proteins of unknown function acting along the same pathway towards this final glycoepitope. [3][4][5] In contrast, GMPPB function is important for the production of GDP mannose, the major mannosyl donor necessary for 4 mannosylation dependent pathways of which aDG mannosylation is one. While there could thus be impairment of multiple GDP-mannose dependent pathways, GMPPB patients do not seem to show the extent of multisystem organ involvement often seen in patients with typical congenital disorders of glycosylation (CDG syndromes).…”

Induction of Antibodies Directed Against Branched Core O‐Mannosyl Glycopeptides—Selectivity Complimentary to the ConA Lectin

“…[6a,11,12b,13] Impaired glycosylation of α-DG has been shown to result in severe congenital muscular dystrophies. [14] …”

“…[6a, 11,12b, 13] Impaired glycosylation of a-DG has been shown to result in severe congenital muscular dystrophies. [14] a-DG was the first O-mannosylated protein found in mammals, however,astudy of O-glycans in total rabbit brain indicated that many more unidentified proteins carry O-mannosyl glycans, and led to the conclusion that about 30 %o ft he released O-glycans werem annosylated. [15] The high abundance of protein O-mannosyl glycans in brain was also showni n as tudy of the mice brain proteome.…”

Facile Chemoenzymatic Synthesis of O‐Mannosyl Glycans

“…Most recently, Cao and co‐workers prepared six core M1 structures ( M100 , M101 , M102 , M104 , M105 , and M102G ) by employing a chemoenzymatic approach . Glycopeptides harboring basic O‐mannosyl structures (e.g., M101 , M102 , core M0, M000 , or core M3) have also been generated. Nevertheless, the majority of O‐mannosyl glycans (especially core M2 branched structures) are still not accessible, which has hampered our in‐depth understanding of O mannosylation.…”