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Human Molecular Genetics Advance Access published online on January 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi062
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

Localisation and Functional Analysis of the LARGE Family of Glycosyltransferases: Significance for Muscular Dystrophy

Martin Brockington 1, Silvia Torelli 1, Paola Prandini 1, Chiara Boito 1, Nazanin Fatima Dolatshad 1, Cheryl Longman 1, Susan C Brown 1, and Francesco Muntoni 2*

1 Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College London, UK
2 Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College, Du Cane Road, London W12 ONN, UK

* To whom correspondence should be addressed.
Francesco Muntoni, E-mail: f.muntoni{at}imperial.ac.uk


  Abstract

The dystroglycanopathies are a novel group of human muscular dystrophies due to mutations in known or putative glycosyltransferase enzymes. They share the common pathological feature of a hypoglycosylated form of {alpha}-dystroglycan, diminishing its ability to bind extracellular matrix ligands. The LARGE glycosyltransferase is mutated in both the myodystrophy mouse and congenital muscular dystrophy type 1D (MDC1D). We have transfected various cell lines with a variety of LARGE expression constructs in order to characterise their subcellular localisation and effect on {alpha}-dystroglycan glycosylation. Wild type LARGE co-localised with the Golgi marker GM130 and stimulated the production of highly glycosylated {alpha}-dystroglycan (hyperglycosylation). MDC1D mutants had no affect {alpha}-dystroglycan glycosylation and failed to localise correctly, confirming their pathogenicity. The two predicted catalytic domains of LARGE contain 3 conserved DxD motifs. Systematically mutating each of these motifs to NNN resulted in the mislocalisation of one construct, while all failed to have any effect on {alpha}-dystroglycan glycosylation. A construct lacking the transmembrane domain also failed to localise at the Golgi apparatus. These results indicate that LARGE needs to both physically interact with {alpha}-dystroglycan and function as a glycosyltransferase in order to stimulate {alpha}-dystroglycan hyperglycosylation. We have also cloned and overexpressed a homologue of LARGE, glycosyltransferase-like 1B (GYLTL1B). Like LARGE it localised to the Golgi apparatus and stimulated {alpha}-dystroglycan hyperglycosylation. These results suggest that GYLTL1B may be a candidate gene for muscular dystrophy and that its overexpression could compensate for the deficiency of both LARGE and other glycosyltransferases.


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