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

Abstract

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 Large(myd)) 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 alpha-dystroglycan in Large(myd) skeletal and cardiac muscle and in brain. We also show that the phenotype of Large(myd) 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 Large(myd) 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 Large(myd) mouse represents an important animal model for studying the function of glycosylation in muscle, brain and retina.

Fukutin-Related Protein Alters the Deposition of Laminin in the Eye and Brain

“…Indeed the radial glia in the FKRP KD cortex often terminated at the sites of ectopic laminin ␣1 deposition. This ectopic deposition of laminin might be expected to disrupt both tangential and radial migration pathways, both of which are altered in patients and dystroglycanopathy mouse models (Holzfeind et al, 2002;Mercuri et al, 2006) and suggests an additional mechanism of disease with respect to the neuronal migration defect observed in patients at the severe end of the clinical spectrum. These observations are further supported by our analyses of BrdU incorporation in the FKRP KD mice which show an accumulation of labeled cells within those areas broadly marked by the ectopic deposition of laminin rather than the marginal zone.…”

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…Therefore, up regulation of this gene might represent a therapeutic approach for the muscular dystrophies caused by defects Congenital muscular dystrophy: Part II reed of alpha-DG glycosyilation 178 . The large myd mouse is an excellent and complete model for glycosylation-deficient CMDs as displays skeletal, cardiac and tongue muscle pathology, defective retinal transmission, and neuronal migration defects 179 . The lArGe homologue, glycosyltransferase-like 1B (GylTl1B), named lArGe2, shows similar sequence and genomic organization and as lArGe-1 is localized in the Golgi apparatus, what suggests its function in glycosylation 29 .…”

Review: Dystroglycan in the Nervous System

“…These mice have a mutation in the gene encoding the glycosyltransferase LARGE, which parallels the mutation in the human disease MDC1D. Besides muscle pathology, myd LARGE mice exhibit eye and brain defects resembling those seen in human myodystrophies (Holzfeind et al, 2002).…”