Human Molecular Genetics, 2002, Vol. 11, No. 21 2673-2687
© 2002 Oxford University Press
Skeletal, cardiac and tongue muscle pathology, defective retinal transmission, and neuronal migration defects in the Largemyd mouse defines a natural model for glycosylation-deficient muscle – eye – brain disorders
1Neuromuscular Research Department, Institute of Anatomy, 2Department of Physiology and 3Brain Research Institute, University of Vienna Medical School, 1090 Vienna, Austria, 4Institute for Laboratory Animal Sciences and Genetics, University of Vienna Medical School, 2325 Himberg, Austria and 5Institute of Genetics, University of Nottingham, Nottingham NG7 2UH, UK
Received July 25, 2002; Accepted August 2, 2002
We have recently shown that a deletion in the Large gene, encoding a putative glycosyltransferase, is the molecular defect underlying the myodystrophy (previously myd; now Largemyd) mouse. Here we show that the muscular dystrophy phenotype is not confined to skeletal muscle, but is also present in the heart and tongue. Immunohistochemistry indicates disruption of the dystrophin-associated glycoprotein complex (DGC) in skeletal and cardiac muscle. Quantitative western blotting shows a general increase in the expression of DGC proteins and of dysferlin and caveolin-3 in mutant skeletal muscle. In contrast, the expression of DGC proteins is reduced in cardiac muscle. Overlay assays show loss of laminin binding by 
-dystroglycan in Largemyd skeletal and cardiac muscle and in brain. We also show that the phenotype of Largemyd mice is not restricted to muscular dystrophy, but also includes ophthalmic and central nervous system (CNS) defects. Electroretinograms of homozygous mutant mice show gross abnormalities of b-wave characteristics, indicative of a complex defect in retinal transmission. The laminar architecture of the cortices of the cerebrum and the cerebellum is disturbed, indicating defective neuronal migration. Thus, the phenotype of the Largemyd mouse shows similarities to the heterogeneous group of human muscle eye brain diseases characterized by severe congenital muscular dystrophy, eye abnormalities and CNS neuronal migration defects. These diseases include Fukuyama-type muscular dystrophy and muscle–eye–brain disease, both of which are also due to mutations in predicted glycosylation enzymes. Therefore, the Largemyd mouse represents an important animal model for studying the function of glycosylation in muscle, brain and retina.
* To whom correspondence should be addressed. Tel: +43 1427761182; Fax: +43 1427761198; Email: reginald.bittner{at}unive.ac.at
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