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Molecular consequences of dominant Bethlem myopathy collagen VI mutations

Baker, Naomi L.; Mörgelin, Matthias LU ; Pace, Rishika A.; Peat, Rachel A.; Adams, Naomi E.; Gardner, R. J. McKinlay; Rowland, Lewis P.; Miller, Geoffrey; De Jonghe, Peter and Ceulemans, Berten, et al. (2007) In Annals of Neurology 62(4). p.390-405
Abstract
Objective: 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. Methods: We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly. Results: Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal... (More)
Objective: 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. Methods: We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly. Results: Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal amount of alpha 1(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. Interpretation: 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. (Less)
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published
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in
Annals of Neurology
volume
62
issue
4
pages
390 - 405
publisher
John Wiley and Sons Inc.
external identifiers
  • wos:000250689300011
  • scopus:36148953276
ISSN
1531-8249
DOI
10.1002/ana.21213
language
English
LU publication?
yes
id
b4e64e78-035a-4237-bde4-339243f06988 (old id 974442)
date added to LUP
2008-01-29 12:57:12
date last changed
2017-11-05 03:29:27
@article{b4e64e78-035a-4237-bde4-339243f06988,
  abstract     = {Objective: 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. Methods: We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly. Results: Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal amount of alpha 1(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. Interpretation: 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.},
  author       = {Baker, Naomi L. and Mörgelin, Matthias and Pace, Rishika A. and Peat, Rachel A. and Adams, Naomi E. and Gardner, R. J. McKinlay and Rowland, Lewis P. and Miller, Geoffrey and De Jonghe, Peter and Ceulemans, Berten and Hannibal, Mark C. and Edwards, Matthew and Thompson, Elizabeth M. and Jacobson, Richard and Quinlivan, Ros C. M. and Aftimos, Salim and Kornberg, Andrew J. and North, Kathryn N. and Bateman, John F. and Lamande, Shireen R.},
  issn         = {1531-8249},
  language     = {eng},
  number       = {4},
  pages        = {390--405},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Annals of Neurology},
  title        = {Molecular consequences of dominant Bethlem myopathy collagen VI mutations},
  url          = {http://dx.doi.org/10.1002/ana.21213},
  volume       = {62},
  year         = {2007},
}