Dystroglycanopathy: From Elucidation of Molecular and Pathological Mechanisms to Development of Treatment Methods

Abstract

Dystroglycanopathy is a collective term referring to muscular dystrophies with abnormal glycosylation of dystroglycan. At least 18 causative genes of dystroglycanopathy have been identified, and its clinical symptoms are diverse, ranging from severe congenital to adult-onset limb-girdle types. Moreover, some cases are associated with symptoms involving the central nervous system. In the 2010s, the structure of sugar chains involved in the onset of dystroglycanopathy and the functions of its causative gene products began to be identified as if they were filling the missing pieces of a jigsaw puzzle. In parallel with these discoveries, various dystroglycanopathy model mice had been created, which led to the elucidation of its pathological mechanisms. Then, treatment strategies based on the molecular basis of glycosylation began to be proposed after the latter half of the 2010s. This review briefly explains the sugar chain structure of dystroglycan and the functions of the causative gene products of dystroglycanopathy, followed by introducing the pathological mechanisms involved as revealed from analyses of dystroglycanopathy model mice. Finally, potential therapeutic approaches based on the pathological mechanisms involved are discussed.

Keywords: dystroglycan; glycosylation; model mouse; muscular dystrophy; ribitol-phosphate; therapy.

Figure 1

Overview of DG sugar chain structure and modifying enzymes. Man, mannose; GlcNAc, N-acetylglucosamine; GalNAc, N-acetylgalactosamine; RboP, ribitol phosphate; Xyl, xylose; GlcA, glucronic acid; Gal, galactose; Rbo5P, ribitol-5-phosphate; POMK, Protein O-mannose kinase; POMGNT, Protein O-mannose N-acetylglucosaminyltransferase; B3GALNT2, β1,3-N-acetylgalactosaminyltransferase 2; TMEM 5, Transmembrane protein 5; RXYLT1, ribitol-5-phosphate xylosyltransferase 1; B4GAT1, β-1,4-glucuronyltransferase 1; LARGE1, like-acetylglucosaminyltransferase 1/ LARGE xylosyl- and glucuronyltransferase 1; POMT, protein O-mannosyl-transferase; FKTN, fukutin; FKRP, Fukutin-related protein; ISPD, isoprenoid synthase domain-containing protein; CRPPA, CDP-ribitol pyrophosphorylase A.

Figure 2

Treatment strategy for ribitol phosphate-deficient DGpathy. DGpathy with ribitol phosphate defects may be treatable. Details are explained in the text.