ORIGINAL ARTICLE

Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy

A K Lampe¹, D M Dunn², A C von Niederhausern², C Hamil², A Aoyagi², S H Laval¹, S K Marie³, M-L Chu⁴, K Swoboda², F Muntoni⁵, C G Bonnemann⁶, K M Flanigan², K M D Bushby¹, R B Weiss²

¹ Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
² Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
³ Department of Medicine, University of São Paulo, São Paulo, Brazil
⁴ Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA
⁵ Dubowitz Neuromuscular Centre, Department of Paediatrics and Neonatal Medicine, Imperial College, London, UK
⁶ The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Correspondence to:
Correspondence to:
Professor Kate Bushby
Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK; Kate.Bushby{at}newcastle.ac.uk

Introduction: Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). BM is a relatively mild dominantly inherited disorder with proximal weakness and distal joint contractures. UCMD is an autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity.

Methods: We developed a method for rapid direct sequence analysis of all 107 coding exons of the COL6 genes using single condition amplification/internal primer (SCAIP) sequencing. We have sequenced all three COL6 genes from genomic DNA in 79 patients with UCMD or BM.

Results: We found putative mutations in one of the COL6 genes in 62% of patients. This more than doubles the number of identified COL6 mutations. Most of these changes are consistent with straightforward autosomal dominant or recessive inheritance. However, some patients showed changes in more than one of the COL6 genes, and our results suggest that some UCMD patients may have dominantly acting mutations rather than recessive disease.

Discussion: Our findings may explain some or all of the cases of UCMD that are unlinked to the COL6 loci under a recessive model. The large number of single nucleotide polymorphisms which we generated in the course of this work may be of importance in determining the major phenotypic variability seen in this group of disorders.

Abbreviations: BM, Bethlem myopathy; PTC, premature termination codon; SCAIP, single condition amplification/internal primer; UCMD, Ullrich congenital muscular dystrophy; vWF, von Willebrand factor

Keywords: Bethlem myopathy; collagen VI; genomic sequencing; Ullrich congenital muscular dystrophy

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