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Human Molecular Genetics Advance Access originally published online on November 24, 2004
Human Molecular Genetics 2005 14(2):279-293; doi:10.1093/hmg/ddi025
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Human Molecular Genetics, Vol. 14, No. 2 © Oxford University Press 2005; all rights reserved

Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy

Naomi L. Baker1, Matthias Mörgelin2, Rachel Peat3, Nathalie Goemans4, Kathryn N. North3, John F. Bateman1 and Shireen R. Lamandé1,*

1Cell and Matrix Biology, Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia, 2Department of Cell and Molecular Biology, Section of Molecular Pathogenesis, Lund University, 221 84 Lund, Sweden, 3Institute for Neuromuscular Research, The Children's Hospital at Westmead and Department of Paediatrics and Child Health, University of Sydney, Australia and 4Department of Paediatric Neurology, University Hospital, Leuven, Belgium

* To whom correspondence should be addressed. Tel: +61 393456650; Fax: +61 393457997; Email: shireen.lamande{at}mcri.edu.au

Received June 1, 2004; Accepted November 11, 2004

Mutations in the three collagen VI genes COL6A1, COL6A2 and COL6A3 cause Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). UCMD, a severe disorder characterized by congenital muscle weakness, proximal joint contractures and marked distal joint hyperextensibility, has been considered a recessive condition, and homozygous or compound heterozygous mutations have been defined in COL6A2 and COL6A3. In contrast, the milder disorder Bethlem myopathy shows clear dominant inheritance and is caused by heterozygous mutations in COL6A1, COL6A2 and COL6A3. This model, where dominant mutations cause mild Bethlem myopathy and recessive mutations cause severe UCMD was recently challenged when a patient with UCMD was shown to have a heterozygous in-frame deletion in COL6A1. We have studied five patients with a clinical diagnosis of UCMD. Three patients had heterozygous in-frame deletions in the N-terminal region of the triple helical domain, one in the {alpha}1(VI) chain, one in {alpha}2(VI) and one in {alpha}3(VI). Collagen VI protein biosynthesis and assembly studies showed that these mutations act in a dominant negative fashion and result in severe collagen VI matrix deficiencies. One patient had recessive amino acid changes in the C2 subdomain of {alpha}2(VI), which prevented collagen VI assembly. No collagen VI mutations were found in the fifth patient. These data demonstrate that rather than being a rare cause of UCMD, dominant mutations are common in UCMD, now accounting for four of the 14 published cases. Mutation detection in this disorder remains critical for accurate genetic counseling of patients and their families.


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