title: Muscular dystrophies due to glycosylation defects.
abstract: 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.
authors.affiliation: Department of Neuroscience, Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom. f.muntoni@ich.ucl.ac.uk
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Silvia
authors.initials: S
authors.lastname: Torelli
authors.forename: Martin
authors.initials: M
authors.lastname: Brockington
mesh_terms: D000818:Animals; D049030:Dystroglycans / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006031:Glycosylation; D006801:Humans; D009154:Mutation / Q000502:physiology; D009223:Myotonic Dystrophy / Q000209:etiology / Q000235:genetics* / Q000628:therapy*
chemical_list: D049030:Dystroglycans