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

Authors: Baker, Naomi L.¹; Mörgelin, Matthias²; Peat, Rachel³; Goemans, Nathalie⁴; North, Kathryn N.³; Bateman, John F.¹; Lamandé, Shireen R.¹

Source: Human Molecular Genetics, Volume 14, Number 2, 15 January 2005 , pp. 279-293(15)

Publisher: Oxford University Press

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Abstract:

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.

Keywords: communicable disease; emergency planning; healthcare associated infections; emerging infections

Document Type: Research article

DOI: http://dx.doi.org/10.1093/hmg/ddi025

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

Publication date: 2005-01-15

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

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