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Human Molecular Genetics Advance Access originally published online on September 9, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 21 2853-2861
DOI: 10.1093/hmg/ddg307
© 2003 Oxford University Press

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 Longman1,{dagger}, Martin Brockington1,{dagger}, Silvia Torelli1, Cecilia Jimenez-Mallebrera1, Colin Kennedy2, Nofal Khalil3, Lucy Feng1, Ravindra K. Saran1,4, Thomas Voit5, Luciano Merlini6, Caroline A. Sewry1,7, Susan C. Brown1 and Francesco Muntoni1,*

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

Received July 24, 2003; Accepted August 29, 2003

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 seven 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 1 bp 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.

* To whom correspondence should be addressed at: Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Campus, Du Cane Road, London W12 ONN, UK. Tel: +44 2083833148; Fax: +44 02087462187; Email: f.muntoni{at}imperial.ac.uk

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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