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Human Molecular Genetics, 2001, Vol. 10, No. 25 2851-2859
© 2001 Oxford University Press

Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C

Martin Brockington1, Yeliz Yuva1, Paola Prandini1, Susan C. Brown1, Silvia Torelli1,2, Matthew A. Benson3, Ralf Herrmann4, Louise V.B. Anderson5, Rumaisa Bashir6, Jean-Marc Burgunder7, Shari Fallet8, Norma Romero9, Michel Fardeau9, Volker Straub4, Gillian Storey6, Christine Pollitt5, Isabelle Richard6, Caroline A. Sewry1,10, Kate Bushby5, Thomas Voit4, Derek J. Blake3 and Francesco Muntoni1,+

1Dubowitz Neuromuscular Centre, Department of Paediatrics, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, UK, 2Department of Cytomorphology, University of Cagliari, Italy, 3Department of Human Anatomy and Genetics, University of Oxford, UK, 4Department of Paediatrics and Paediatric Neurology, University of Essen, Germany, 5Department of Biochemistry and Genetics, University of Newcastle upon Tyne, UK, 6Department of Biological Sciences, University of Durham, UK, 7University Bern Inselspital, CH-3010 Bern, Switzerland, 8Children’s Hospital of New Jersey, Newark, USA, 9Inserm U 523, Institut De Myologie, Groupe Hospitalier Pitie-Salpetriere, Paris, France and 10Department of Histopathology, Robert Jones and Agnes Hunt, Orthopaedic Hospital, Oswestry, UK

The limb girdle and congenital muscular dystrophies (LGMD and CMD) are characterized by skeletal muscle weakness and dystrophic muscle changes. The onset of symptoms in CMD is within the first few months of life, whereas in LGMD they can occur in late childhood, adolescence or adult life. We have recently demonstrated that the fukutin-related protein gene (FKRP) is mutated in a severe form of CMD (MDC1C), characterized by the inability to walk, leg muscle hypertrophy and a secondary deficiency of laminin {alpha}2 and {alpha}-dystroglycan. Both MDC1C and LGMD2I map to an identical region on chromosome 19q13.3. To investigate whether these are allelic disorders, we undertook mutation analysis of FKRP in 25 potential LGMD2I families, including some with a severe and early onset phenotype. Mutations were identified in individuals from 17 families. A variable reduction of {alpha}-dystroglycan expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin {alpha}2 either by immunocytochemistry or western blotting. Unexpectedly, affected individuals from 15 families had an identical C826A (Leu276Ileu) mutation, including five that were homozygous for this change. Linkage analysis identified at least two possible haplotypes in linkage disequilibrium with this mutation. Patients with the C826A change had the clinically less severe LGMD2I phenotype, suggesting that this is a less disruptive FKRP mutation than those found in MDC1C. The spectrum of LGMD2I phenotypes ranged from infants with an early presentation and a Duchenne-like disease course including cardiomyopathy, to milder phenotypes compatible with a favourable long-term outcome.

+ To whom correspondence should be addressed at: The Dubowtz Neuromuscular Unit, Division of Paediatrics, Obstetrics and Gynaecology, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Tel: +44 20 8383 3295; Fax: +44 20 8740 8281; Email: f.muntoni@ic.ac.uk


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