International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Plenary Presentations * Oral Presentations *
Poster Presentations: Complex Genetics and Disease Modifiers * Developmental Genetics * Functional Genomics * Gene Discovery * Genetic Manipulations to Alter Gene Function * Mouse Models: Human Disease and Pharmacogenetics * Sequence Annotation and Comparative Analysis of Genomes *
Attendees * Sponsors * Table of Contents * Photographs * Awards

Oral Presentation

Wednesday 20 November

16:15 - 16:30 HRS

MUTATED GLYCOSYLTRANSFERASE AND HYPOGLYCOSYLATION OF ALPHA-DYSTROGLYCAN IN THE LARGEMYD MOUSE: A MODEL FOR GLYCOSYLATION-DEFICIENT MUSCULAR DYSTROPHIES

P Grewal
University of Nottingham

Co-Authors: 2) Holzfiend P,  2) Reitsamer H, 2) Kechvar J, 2) Lassmann H, 2) Höger H, 2) Bittner R,  1) Hewitt J
Institutions: 1) University of Nottingham, 2) University of Vienna

The myodystrophy mouse is a spontaneous, autosomal recessive model of muscular dystrophy. We previously identified the molecular defect underlying the myodystrophy (Largemyd) mouse as a deletion in the Large gene, encoding a glycosyltransferase. This mutant is currently the only animal model for studying the role of glycosylation in the group of human muscle disorders due to mutated glycosyltransferases.Dystroglycan, an extensively modified glycoprotein, is a central component of the dystrophin-associated glycoprotein complex; this plays an important role in maintaining muscle membrane integrity. Furthermore, glycosylation of ?lpha?dystroglycan is necessary for its interaction with the extracellular matrix protein laminin. Western analyses of Largemyd proteins reveal hypo-glycosylation of alpha-dystroglycan and loss of laminin binding. We are currently using the glycan-binding specificities of lectins to investigate the overall glycosylation profile of Largemyd proteins and to characterise the alterations in alpha-dystroglycan sugars. Lectin immunoblot overlays and affinity chromatography suggests there is not a general loss of particular carbohydrate structures in Largemyd tissues, rather a specific alteration in glycosylation of a small number of glycoproteins with alpha-dystroglycan being one of the primary target proteins of Large.Altered (hypo) glycosylation of alpha-dystroglycan has since been reported as a feature of four inherited human muscular dystrophies. We extend the phenotype of Largemyd mice to include ophthalmic and central nervous system defects thereby showing similarities to the human disorders characterised by severe congenital muscular dystrophy, eye abnormalities and CNS neuronal migration defects: Fukuyama congenital muscular dystrophy and muscle-eye-brain disease, both of which are due to mutations in glycosylation enzymes.