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Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy
  1. A K Lampe1,
  2. D M Dunn2,
  3. A C von Niederhausern2,
  4. C Hamil2,
  5. A Aoyagi2,
  6. S H Laval1,
  7. S K Marie3,
  8. M-L Chu4,
  9. K Swoboda2,
  10. F Muntoni5,
  11. C G Bonnemann6,
  12. K M Flanigan2,
  13. K M D Bushby1,
  14. R B Weiss2
  1. 1Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
  2. 2Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
  3. 3Department of Medicine, University of São Paulo, São Paulo, Brazil
  4. 4Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA
  5. 5Dubowitz Neuromuscular Centre, Department of Paediatrics and Neonatal Medicine, Imperial College, London, UK
  6. 6The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
  1. 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;


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.

  • BM, Bethlem myopathy
  • PTC, premature termination codon
  • SCAIP, single condition amplification/internal primer
  • UCMD, Ullrich congenital muscular dystrophy
  • vWF, von Willebrand factor
  • Bethlem myopathy
  • collagen VI
  • genomic sequencing
  • Ullrich congenital muscular dystrophy

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  • This work was supported by MDC (Muscular Dystrophy Campaign) financial aid to the Newcastle Muscle Centre, Myocluster and MDC grants to FM as well as NIH grant AR38912 to MLC. KMF is supported by NIH grants M01 RR00064-39 and R01 NS043264-03. CGB is a Pew Scholar in the Biomedical Sciences. He is also supported by an Ethel Brown Foerder award and by the Florence R.C. Murray Fellowship Program at the Children’s Hospital of Philadelphia. AKL gratefully acknowledges funding by a Wellcome Entry Level Fellowship and subsequently by a Patrick Berthoud Fellowship. SL is funded by the MDC.

  • Conflict of interest: none declared.