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Defective O-mannosyl glycan synthesis in dystroglycanopathies: pathogenesis and therapeutic frontiers

Journal of Human Genetics (2025)Cite this article

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Dystroglycanopathies are a group of congenital muscular dystrophies caused by defects in the glycosylation of α-dystroglycan, a critical component of the dystrophin–glycoprotein complex linking the extracellular matrix to the cytoskeleton. Defective synthesis or elongation of the unique O-mannosyl glycan-derived structure matriglycan essential for ligand binding to α-dystroglycan is central to disease pathology. These disorders result from pathogenic variants in the genes involved in glycan biosynthesis, including those encoding enzymes involved in phospho-core M3 formation, ribitol phosphate modification, and matriglycan polymerization. Their clinical spectrum ranges from congenital muscular dystrophy with central nervous system abnormalities to adult-onset limb–girdle muscular dystrophy. Recent studies have enhanced our understanding of dystroglycan roles in muscle regeneration, cardiac function, and brain development. Based on these insights, several therapeutic strategies, including gene therapy, use of antisense oligonucleotides, and substrate supplementation, are currently being explored for new treatment avenues. In this review, we discuss the mechanisms of dystroglycan glycosylation and molecular pathology of dystroglycanopathies and highlight the recent advances in dystroglycanopathy treatment.

Dystroglycan consists of an α-subunit (α-dystroglycan), which is located extracellularly and functions as a receptor for basement membrane proteins, and a β-subunit (β-dystroglycan), which is a transmembrane protein [3]. β-Dystroglycan anchors α-dystroglycan to the cell membrane and binds to dystrophin in the cell, contributing to DGC formation. O-mannosyl (O-Man) glycans are necessary for α-dystroglycan binding to the extracellular matrix components, such as laminin [4]. In dystroglycanopathies, defective synthesis of O-Man glycans prevents laminin from binding to α-dystroglycan, resulting in impaired DGC function, which is a major cause of the disease pathology. Notably, O-Man glycans in mammals were first identified on dystroglycan. Initially considered to be a rare type of O-glycans, they are now known to be among the major types of O-glycans [5]. Other glycoproteins modified by O-Man have also been identified [6, 7]. Known ligands for α-dystroglycan include the extracellular matrix components, such as laminin and perlecan, and synaptic molecules, such as neurexin, agrin, and pikachurin [8,9,10,11,12,13]. These reports highlight the vital importance O-Man glycan modifications for binding to these ligands.

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Fig. 1: Dystrophin–glycoprotein complex (DGC) and dystroglycanopathies.
Fig. 2: Structural diversity and biosynthesis of core M1/M2/M3 glycans in mammals.

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Authors and Affiliations

  1. Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-ku, Tokyo, Japan

    Hiroshi Manya

  2. Department of Cell Biology and Molecular Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan

    Motoi Kanagawa

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  1. Hiroshi Manya
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Correspondence to Hiroshi Manya.

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MK reports receiving a collaborative research grant from JCR Pharmaceuticals Co Ltd.

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Manya, H., Kanagawa, M. Defective O-mannosyl glycan synthesis in dystroglycanopathies: pathogenesis and therapeutic frontiers. J Hum Genet (2025). https://doi.org/10.1038/s10038-025-01387-1

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