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Human Molecular Genetics Advance Access published online on September 9, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg307
© 2003 by Oxford University Press
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©2003 Oxford University Press

Article

Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of {alpha}-dystroglycan

Cheryl Longman 1, Martin Brockington 1, Silvia Torelli 1, Cecilia Jimenez-Mallebrera 1, Colin Kennedy 2, Nofal Khalil 3, Lucy Feng 1, Ravindra K Saran 4, Thomas Voit 5, Luciano Merlini 6, Caroline A Sewry 7, Susan C Brown 1, and Francesco Muntoni 8*

1 Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Campus, London, UK
2 Paediatric Neurology Department, Southampton General Hospital, UK
3 Neurophysiology Department, Hammersmith Hospital, London, UK
4 Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Campus, London, UK; Department of Pathology, G.B.Pant Hospital, Maulana Azad Medical College, New Delhi, India
5 Department of Paediatrics and Paediatric Neurology, University of Essen, Germany
6 Neuromuscular Unit, Istituto Ortopedico Rizzoli, Bologna, Italy
7 Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Campus, London, UK; Department of Histopathology, RJAH Orthopaedic Hospital, Oswestry, UK
8 Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Campus, Du Cane Road, London W12 ONN, UK

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


  Abstract

The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders. A new pathomechanism has recently been identified in a group of these disorders in which known or putative glycosyltransferases are defective. Common to all these conditions is the hypoglycosylation of {alpha}-dystroglycan. Fukuyama CMD, Muscle-Eye-Brain disease and Walker-Warburg syndrome, each associated with eye abnormalities and neuronal migration defects, result from mutations in fukutin, POMGnT1 and POMT1 respectively, while mutations in the fukutin-related protein (FKRP) gene cause congenital muscular dystrophy 1C, typically lacking brain involvement. Another putative glycosyltransferase, Large, is mutated in the myodystrophy mouse. The human homologue of this gene is therefore a strong candidate for involvement in novel forms of muscular dystrophy. We studied 36 patients with muscular dystrophy and either mental retardation, structural brain changes or abnormal {alpha}-dystroglycan immunolabelling, unlinked to any reported CMD loci. Linkage analysis in 7 informative families excluded involvement of LARGE but sequencing of this gene in the remaining 29 families identified one patient with a G1525A (Glu509Lys) missense mutation and a 1bp insertion, 1999insT. This 17 year old girl presented with congenital muscular dystrophy, profound mental retardation, white matter changes and subtle structural abnormalities on brain MRI. Her skeletal muscle biopsy showed reduced immunolabelling of {alpha}-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced molecular weight form of {alpha}-dystroglycan that retained some laminin binding activity. This is the first description of mutations in the human LARGE gene and we propose to name this new disorder MDC1D.


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