Collagen VI glycine mutations: Perturbed assembly and a spectrum of clinical severity
Rishika A. Pace BSc(Hons)
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorRachel A. Peat PhD
Institute for Neuromuscular Research, Children's Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, New South Wales, Australia
Search for more papers by this authorNaomi L. Baker PhD
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorLaura Zamurs PhD
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorMatthias Mörgelin PhD
Department of Clinical Sciences, Lund University, Lund, Sweden
Search for more papers by this authorMelita Irving MBBS
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorNaomi E. Adams BSc(Hons)
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorJohn F. Bateman PhD
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorDavid Mowat MBBS
Department of Medical Genetics, Sydney Children's Hospital, New South Wales
Search for more papers by this authorNicholas J. C. Smith MBBS
Department of Neurology, Sydney Children's Hospital, New South Wales
Search for more papers by this authorPhillipa J. Lamont MBBS, PhD
Neurogenetics Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia
Search for more papers by this authorSteven A. Moore MD, PhD
Department of Pathology, University of Iowa, Iowa City, IA
Iowa Wellstone Muscular Dystrophy Cooperative Research Center, Iowa City, IA
Search for more papers by this authorKatherine D. Mathews MD
Department of Pediatrics, University of Iowa, Iowa City, IA
Iowa Wellstone Muscular Dystrophy Cooperative Research Center, Iowa City, IA
Search for more papers by this authorKathryn N. North MBBS, MD
Institute for Neuromuscular Research, Children's Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Shireen R. Lamandé PhD
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville 3052, Victoria, AustraliaSearch for more papers by this authorRishika A. Pace BSc(Hons)
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorRachel A. Peat PhD
Institute for Neuromuscular Research, Children's Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, New South Wales, Australia
Search for more papers by this authorNaomi L. Baker PhD
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorLaura Zamurs PhD
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorMatthias Mörgelin PhD
Department of Clinical Sciences, Lund University, Lund, Sweden
Search for more papers by this authorMelita Irving MBBS
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorNaomi E. Adams BSc(Hons)
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorJohn F. Bateman PhD
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Search for more papers by this authorDavid Mowat MBBS
Department of Medical Genetics, Sydney Children's Hospital, New South Wales
Search for more papers by this authorNicholas J. C. Smith MBBS
Department of Neurology, Sydney Children's Hospital, New South Wales
Search for more papers by this authorPhillipa J. Lamont MBBS, PhD
Neurogenetics Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia
Search for more papers by this authorSteven A. Moore MD, PhD
Department of Pathology, University of Iowa, Iowa City, IA
Iowa Wellstone Muscular Dystrophy Cooperative Research Center, Iowa City, IA
Search for more papers by this authorKatherine D. Mathews MD
Department of Pediatrics, University of Iowa, Iowa City, IA
Iowa Wellstone Muscular Dystrophy Cooperative Research Center, Iowa City, IA
Search for more papers by this authorKathryn N. North MBBS, MD
Institute for Neuromuscular Research, Children's Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Shireen R. Lamandé PhD
Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia
Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville 3052, Victoria, AustraliaSearch for more papers by this authorAbstract
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. Ann Neurol 2008
Supporting Information
This article includes supplementary materials available via the Internet at http://www.interscience.wiley.com/jpages/0364-5134/suppmat
| Filename | Description |
|---|---|
| ana21439-PaceSupplementaryFig1.tif12.5 MB | Figure S1.UCMD fibroblasts secrete non-disulfide bonded tetramers. Control (S289) and UCMD fibroblasts (U8, U9, U20, U38, U41 and U46) were biosynthetically labeled overnight with [ 35 S]methionine and aliquots of the medium separated under native conditions on a Superose 6 10/300 GL column. Collagen VI in the eluted fractions was immunoprecipitated and analysed under non-reducing conditions on composite agarose-acrylamide gels. Collagen VI tetramers eluted predominantly in fractions 16-17 and fibronectin dimers (FN 2 ), which bind non-specifically to protein A-Sepharose, eluted in fractions 20-23. Collagen VI migrating as dimers is apparent in UCMD fractions 16 and 17; however, dimers are not eluted in later fractions indicating that under native conditions they are the same size as tetramers. |
| ana21439-PaceSupplementaryTables.doc262.5 KB | Supporting Information file ana21439-PaceSupplementaryTables.doc |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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