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Collagen VI glycine mutations: Perturbed assembly and a spectrum of clinical severity

Pace, Rishika A.; Peat, Rachel A.; Baker, Naomi L.; Zamurs, Laura; Mörgelin, Matthias LU ; Irving, Melita; Adams, Naomi E.; Bateman, John F.; Mowat, David and Smith, Nicholas J. C., et al. (2008) In Annals of Neurology 64(3). p.294-303
Abstract
Objective: The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes. Methods: We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway. Results: All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI... (More)
Objective: The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes. Methods: We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway. Results: All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The second group had more severe assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced. Interpretation: These data indicate that collagen VI glycine mutations impair the assembly pathway in different ways and disease severity correlates with the assembly abnormality. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate-to-severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. This study thus provides an explanation for how different glycine mutations produce a spectrum of clinical severity. (Less)
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published
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in
Annals of Neurology
volume
64
issue
3
pages
294 - 303
publisher
John Wiley and Sons Inc.
external identifiers
  • wos:000259681700012
  • scopus:54849438119
ISSN
1531-8249
DOI
10.1002/ana.21439
language
English
LU publication?
yes
id
205967d9-4483-4212-aa91-826540612a14 (old id 1286899)
date added to LUP
2009-01-29 15:11:40
date last changed
2017-01-01 04:22:34
@article{205967d9-4483-4212-aa91-826540612a14,
  abstract     = {Objective: The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes. Methods: We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway. Results: All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The second group had more severe assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced. Interpretation: These data indicate that collagen VI glycine mutations impair the assembly pathway in different ways and disease severity correlates with the assembly abnormality. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate-to-severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. This study thus provides an explanation for how different glycine mutations produce a spectrum of clinical severity.},
  author       = {Pace, Rishika A. and Peat, Rachel A. and Baker, Naomi L. and Zamurs, Laura and Mörgelin, Matthias and Irving, Melita and Adams, Naomi E. and Bateman, John F. and Mowat, David and Smith, Nicholas J. C. and Lamont, Phillipa J. and Moore, Steven A. and Mathews, Katherine D. and North, Kathryn N. and Lamande, Shireen R.},
  issn         = {1531-8249},
  language     = {eng},
  number       = {3},
  pages        = {294--303},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Annals of Neurology},
  title        = {Collagen VI glycine mutations: Perturbed assembly and a spectrum of clinical severity},
  url          = {http://dx.doi.org/10.1002/ana.21439},
  volume       = {64},
  year         = {2008},
}