International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


MURINE MUSCULAR DYSTROPHY PHENOTYPE CAUSED BY A GLYCOSYLTRANSFERASE MUTATION AND DISRUPTION OF THE DYSTROPHIN ASSOCIATED GLYCOPROTEIN COMPLEX

Pam Grewal
Institute of Genetics
Queen's Medical Centre
University of Nottingham
Nottingham NG7 2UH UK

Co-Authors: 1)Bittner R, 2)Hewitt J
Institutions: 1)Institute of Neuromuscular Research Department, University of Vienna, 2)Institute of Genetics, Queen's Medical Centre, University of Nottingham

The autosomal recessive mouse mutation myodystrophy (myd) produces a severe, progressive muscular dystrophy phenotype. High-resolution comparative mapping showed myd maps to the region of MMU8 displaying homology to HSA19p13 and 22q12. The availability of ordered draft and finished sequence data for these two chromosomes and homologous mouse genomic regions allowed us to use a database-facilitated approach to develop a gene map around the myd locus.

Using this comparative, positional cloning approach, we identified the gene mutated in myd as a glycosyltransferase (Large). In myd, an intragenic deletion removes three exons, producing a frameshift and premature termination of the protein. Given the specific muscular phenotype of myd mice, we hypothesised that the target of this glycosyltransferase might be a component of the dystrophin associated glycoprotein complex (DGC). Mutations in various components of the DGC are associated with muscular dystrophy in humans and rodents. Western blotting data suggests glycosylation of a-DG is markedly reduced in myd mice. We are currently investigating our finding that the abnormal dystroglycan in myd has altered affinity for laminin in skeletal and cardiac muscle. The underglycosylation of this key component of the DGC resulting in a reduced affinity for laminin could possibly be the pivotal event that effects their dystrophic phenotype.


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