Muscular dystrophies due to glycosylation defects

Abstract

Summary:In the last few years, muscular dystrophies due to reduced glycosylation of alpha-dystroglycan (ADG) have emerged as a common group of conditions, now referred to as dystroglycanopathies. Mutations in six genes (POMT1, POMT2, POMGnT1, Fukutin, FKRP and LARGE) have so far been identified in patients with a dystroglycanopathy. Allelic mutations in each of these genes can result in a wide spectrum of clinical conditions, ranging from severe congenital onset with associated structural brain malformations (Walker Warburg syndrome; muscle-eye-brain disease; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D) to a relatively milder congenital variant with no brain involvement (congenital muscular dystrophy type 1C), and to limb-girdle muscular dystrophy (LGMD) type 2 variants with onset in childhood or adult life (LGMD2I, LGMD2L, and LGMD2N).ADG is a peripheral membrane protein that undergoes multiple and complex glycosylation steps to regulate its ability to effectively interact with extracellular matrix proteins, such as laminin, agrin, and perlecan.Although the precise composition of the glycans present on ADG are not known, it has been demonstrated that the forced overexpression of LARGE, or its paralog LARGE2, is capable of increasing the glycosylation of ADG in normal cells. In addition, its overexpression is capable of restoring dystroglycan glycosylation and laminin binding properties in primary cell cultures of patients affected by different genetically defined dystroglycanopathy variants.These observations suggest that there could be a role for therapeutic strategies to overcome the glycosylation defect in these conditions via the overexpression of LARGE.

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

“…The generally accepted role for this complex is to act as a molecular shock absorber and stabilize the plasma membrane during muscle contraction. Disruption of the DGC's linkage between the cytoskeleton and extracellular matrix, such as occurs in DMD (1,(5)(6)(7) or with the disruption of α-dystroglycan-laminin binding in glycosylation-deficient muscular dystrophies (8,9), leads to destabilization of the plasma membrane, rendering skeletal muscle fibers and cardiomyocytes susceptible to stretch-or contraction-induced injury and cell death (10)(11)(12)(13)(14).…”

Human Natural Killer-1 Sulfotransferase (HNK-1ST)-induced Sulfate Transfer Regulates Laminin-binding Glycans on α-Dystroglycan

“…␣-DG undergoes extensive glycosylation in a tissue-specific manner (18,19,21), and the attached glycan acts as a critical mediator of the interaction between ␣-DG and its ligands (22,23). Although the precise structure of the glycan important for the function of ␣-DG has not completely been determined, aberrant glycosylation of ␣-DG has already been identified in the pathogenesis of several types of congenital muscular dystrophy (CMD) accompanied by brain and eye malformations (24,25). In CMD patients, mutations in six known or putative glycosyltransferase genes involved in the biosynthesis of O-mannosyl glycan, including protein O-mannosyltransferase 1 (POMT1), POMT2, protein O-mannose ␤-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1), fukutin, fukutin-related protein (FKRP), and likeacetylglucosaminyltransferase (LARGE), have been found (26 -31).…”

The O-Mannosylation Pathway: Glycosyltransferases and Proteins Implicated in Congenital Muscular Dystrophy

“…The protein substrates for the O-mannosylation pathway have yet to be elucidated, with only a few putative proteins besides ␣-dystroglycan being identified to date. This may be particularly important given that the phenotypes observed in the dystroglycanopathies clearly overlap but also exceed those observed in Duchenne muscular dystrophy (65,78). Thus, like all good science, the cohort of scientists/clinicians in this field have made substantial advances while creating more questions that need to be pursued if we are to better understand the disease-relevant pathway of protein O-mannosylation.…”