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Type: Journal article
Title: Molecular consequences of dominant Bethlem myopathy collagen VI mutations
Author: Baker, N.
Morgelin, M.
Pace, R.
Peat, R.
Adams, N.
Gardner, R.
Rowland, L.
Miller, G.
De Jonghe, P.
Ceulemans, B.
Hannibal, M.
Edwards, M.
Thompson, E.
Jacobson, R.
Quinlivan, R.
Aftimos, S.
Kornberg, A.
North, K.
Bateman, J.
Lamande, S.
Citation: Annals of Neurology, 2007; 62(4):390-405
Publisher: Wiley-Liss
Issue Date: 2007
ISSN: 0364-5134
1531-8249
Statement of
Responsibility: 
Naomi L. Baker, Matthias Mörgelin, Rishika A. Pace, Rachel A. Peat, Naomi E. Adams, R. J. McKinlay Gardner, Lewis P. Rowland, Geoffrey Miller, Peter De Jonghe, Berten Ceulemans, Mark C. Hannibal, Matthew Edwards, Elizabeth M. Thompson, Richard Jacobson, Ros C. M. Quinlivan, Salim Aftimos, Andrew J. Kornberg, Kathryn N. North, John F. Bateman, Shireen R. Lamandé
Abstract: <h4>Objective</h4>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.<h4>Methods</h4>We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly.<h4>Results</h4>Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal amount of alpha1(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.<h4>Interpretation</h4>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.
Keywords: Humans
Muscular Diseases
Collagen Diseases
Genetic Predisposition to Disease
Collagen Type VI
Genes, Dominant
Mutation
Polymorphism, Single Nucleotide
Adult
Middle Aged
Female
Male
Rights: Copyright © 2007 American Neurological Association
DOI: 10.1002/ana.21213
Appears in Collections:Aurora harvest 6
Paediatrics publications

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