Brain Advance Access originally published online on September 18, 2007
Brain 2007 130(10):2725-2735; doi:10.1093/brain/awm212
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refining genotype–phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan
1Dubowitz Neuromuscular Unit, Hammersmith Hospital, Imperial College, London, 2DNA Laboratory, Genetics Centre, Guy's Hospital, London, UK, 3The Institute for Neuromuscular Research, The Children's Hospital at Westmead, University of Sydney, Australia, 4Department of Paediatric Pathology, Hacettepe Children's Hospital, Ankara, Turkey, 5Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Newcastle upon Tyne, 6Centre for Inherited Neuromuscular Disorders, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK and 7Department of Child Neurology, Hacettepe Children's Hospital, Ankara, Turkey
Correspondence to: Francesco Muntoni, Department of Paediatrics, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12ONN, UK E-mail: f.muntoni{at}ic.ac.uk
Muscular dystrophies with reduced glycosylation of 
-dystroglycan (-DG), commonly referred to as dystroglycanopathies, are a heterogeneous group of autosomal recessive conditions which include a wide spectrum of clinical severity. Reported phenotypes range from severe congenital onset Walker–Warburg syndrome (WWS) with severe structural brain and eye involvement, to relatively mild adult onset limb girdle muscular dystrophy (LGMD). Specific clinical syndromes were originally described in association with mutations in any one of six demonstrated or putative glycosyltransferases. Work performed on patients with mutations in the FKRP gene has identified that the spectrum of phenotypes due to mutations in this gene is much wider than originally assumed. To further define the mutation frequency and phenotypes associated with mutations in the other five genes, we studied a large cohort of patients with evidence of a dystroglycanopathy. Exclusion of mutations in FKRP was a prerequisite for participation in this study. Ninety-two probands were screened for mutations in POMT1, POMT2, POMGnT1, fukutin and LARGE. Homozygous and compound heterozygous mutations were detected in a total of 31 probands (34 individuals from 31 families); 37 different mutations were identified, of which 32 were novel. Mutations in POMT2 were the most prevalent in our cohort with nine cases, followed by POMT1 with eight cases, POMGnT1 with seven cases, fukutin with six cases and LARGE with only a single case. All patients with POMT1 and POMT2 mutations had evidence of either structural or functional central nervous system involvement including four patients with mental retardation and a LGMD phenotype. In contrast mutations in fukutin and POMGnT1 were detected in four patients with LGMD and no evidence of brain involvement. The majority of patients (six out of nine) with mutations in POMT2 had a Muscle–Eye–Brain (MEB)-like condition. In addition we identified a mutation in the gene LARGE in a patient with WWS.
Our data expands the clinical phenotypes associated with POMT1, POMT2, POMGnT1, fukutin and LARGE mutations. Mutations in these five glycosyltransferase genes were detected in 34% of patients indicating that, after the exclusion of FKRP, the majority of patients with a dystroglycanopathy harbour mutations in novel genes.
Key Words: congenital muscular dystrophy; limb girdle muscular dystrophy; alpha dystroglycan; glycosylation; glycosyltransferase
Abbreviations:
CMD, congenital muscular dystrophy; LGMD, limb girdle muscular dystrophy; -DG, alpha-dystroglycan
.
Received May 11, 2007. Revised August 9, 2007. Accepted August 10, 2007.
*These authors contributed equally to this work.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Otto, C. Schmidt, G. Luke, S. Allen, P. Valasek, F. Muntoni, D. Lawrence-Watt, and K. Patel Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal muscle regeneration J. Cell Sci., September 1, 2008; 121(17): 2939 - 2950. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lommel, T. Willer, and S. Strahl POMT2, a key enzyme in Walker-Warburg syndrome: somatic sPOMT2, but not testis-specific tPOMT2, is crucial for mannosyltransferase activity in vivo Glycobiology, August 1, 2008; 18(8): 615 - 625. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Peat, J. M. Smith, A. G. Compton, N. L. Baker, R. A. Pace, D. J. Burkin, S. J. Kaufman, S. R. Lamande, and K. N. North Diagnosis and etiology of congenital muscular dystrophy Neurology, July 29, 2008; 71(5): 312 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. P. Wairkar, L. G. Fradkin, J. N. Noordermeer, and A. DiAntonio Synaptic Defects in a Drosophila Model of Congenital Muscular Dystrophy J. Neurosci., April 2, 2008; 28(14): 3781 - 3789. [Abstract] [Full Text] [PDF]
|
|