Molecular consequences of dominant Bethlem myopathy collagen VI mutations
Article first published online: 20 SEP 2007
Copyright © 2007 American Neurological Association
Annals of Neurology
Volume 62, Issue 4, pages 390–405, October 2007
How to Cite
Baker, N. L., Mörgelin, M., Pace, R. A., Peat, R. A., Adams, N. E., Gardner, R. J. M., Rowland, L. P., Miller, G., De Jonghe, P., Ceulemans, B., Hannibal, M. C., Edwards, M., Thompson, E. M., Jacobson, R., Quinlivan, R. C. M., Aftimos, S., Kornberg, A. J., North, K. N., Bateman, J. F. and Lamandé, S. R. (2007), Molecular consequences of dominant Bethlem myopathy collagen VI mutations. Ann Neurol., 62: 390–405. doi: 10.1002/ana.21213
- Issue published online: 29 OCT 2007
- Article first published online: 20 SEP 2007
- Manuscript Accepted: 16 JUL 2007
- Manuscript Revised: 21 JUN 2007
- Manuscript Received: 30 MAR 2007
- National Health and Medical Research Council of Australia. Grant Number: 284533
- Dora Lush Postgraduate Training Fellowships
- Murdoch Childrens Research Institute, an Australian Postgraduate Award
- University of Melbourne Solander Fellowship
Dominant mutations in the three collagen VI genes cause Bethlem myopathy, a disorder characterized by proximal muscle weakness and commonly contractures of the fingers, wrists, and ankles. Although more than 20 different dominant mutations have been identified in Bethlem myopathy patients, the biosynthetic consequences of only a subset of these have been studied, and in many cases, the pathogenic mechanisms remain unknown.
We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly.
Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal amount of α1(VI) messenger RNA and reduced amounts of collagen VI protein. Two patients had a previously reported mutation causing skipping of COL6A1 exon 14, and three patients had novel mutations leading to in-frame deletions toward the N-terminal end of the triple-helical domain. These mutations have different and complex effects on collagen VI intracellular and extracellular assembly. Two patients had single amino acid substitutions in the A-domains of COL6A2 and COL6A3. Collagen VI intracellular and extracellular assembly was normal in one of these patients.
The key to dissecting the pathogenic mechanisms of collagen VI mutations lies in detailed analysis of collagen VI biosynthesis and assembly. The majority of mutations result in secretion and deposition of structurally abnormal collagen VI. However, one A-domain mutation had no detectable effect on assembly, suggesting that it acts by compromising collagen VI interactions in the extracellular matrix of muscle. Ann Neurol 2007