Journal article
Collagen VI Glycine Mutations : Perturbed Assembly and a Spectrum of Clinical Severity
Annals of neurology, Vol.64(3), pp.294-303
2008
DOI: 10.1002/ana.21439
PMCID: PMC2743946
PMID: 18825676
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.
Details
- Title: Subtitle
- Collagen VI Glycine Mutations : Perturbed Assembly and a Spectrum of Clinical Severity
- Creators
- Rishika A PACE - Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, AustraliaRachel A PEAT - Institute for Neuromuscular Research, Children's Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, New South Wales, AustraliaPhillipa J LAMONT - Neurogenetics Unit, Department of Neurology, Royal Perth Hospital, Perth, AustraliaSteven A MOORE - Department of Pathology, University of Iowa, United StatesKatherine D MATHEWS - Iowa Wellstone Muscular Dystrophy Cooperative Research Center, Iowa City, IA, United StatesKathryn N NORTH - Institute for Neuromuscular Research, Children's Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, New South Wales, AustraliaShireen R LAMANDE - Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, AustraliaNaomi L BAKER - Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, AustraliaLaura ZAMURS - Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, AustraliaMatthias MÖRGELIN - Department of Clinical Sciences, Lund University, Lund, SwedenMelita IRVING - Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, AustraliaNaomi E ADAMS - Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, AustraliaJohn F BATEMAN - Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, AustraliaDavid MOWAT - Department of Medical Genetics, Sydney Children's Hospital, New South Wales, AustraliaNicholas J. C SMITH - Department of Neurology, Sydney Children's Hospital, New South Wales, Australia
- Resource Type
- Journal article
- Publication Details
- Annals of neurology, Vol.64(3), pp.294-303
- DOI
- 10.1002/ana.21439
- PMID
- 18825676
- PMCID
- PMC2743946
- NLM abbreviation
- Ann Neurol
- ISSN
- 0364-5134
- eISSN
- 1531-8249
- Publisher
- Willey-Liss; Hoboken
- Grant note
- name: National Health and Medical Research Council of Australia, award: 284533; name: NH & MRC Dora Lush Biomedical Research Scholarship, award: 249429; name: Melbourne Research Scholarship; name: Muscular Dystrophy Association USA, award: MDA4076; name: Murdoch Childrens Research Institute; name: University of Melbourne Solander Fellowship; DOI: 10.13039/100000065, name: NIH (National Institute of Neurological Disorders and Stroke), award: NS053672
- Language
- English
- Date published
- 2008
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984014018802771
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