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Molecular consequences of dominant Bethlem myopathy collagen VI mutations

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 biosy... Full description

Journal Title: Annals of Neurology October 2007, Vol.62(4), pp.390-405
Main Author: Baker, Naomi L.
Other Authors: Mörgelin, Matthias , Pace, Rishika A. , Peat, Rachel A. , Adams, Naomi E. , Gardner, R. J. Mckinlay , Rowland, Lewis P. , Miller, Geoffrey , De Jonghe, Peter , Ceulemans, Berten , Hannibal, Mark C. , Edwards, Matthew , Thompson, Elizabeth M. , Jacobson, Richard , Quinlivan, Ros C. M. , Aftimos, Salim , Kornberg, Andrew J. , North, Kathryn N. , Bateman, John F. , Lamandé, Shireen R.
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0364-5134 ; E-ISSN: 1531-8249 ; DOI: 10.1002/ana.21213
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title: Molecular consequences of dominant Bethlem myopathy collagen VI mutations
format: Article
creator:
  • Baker, Naomi L.
  • Mörgelin, Matthias
  • Pace, Rishika A.
  • Peat, Rachel A.
  • Adams, Naomi E.
  • Gardner, R. J. Mckinlay
  • Rowland, Lewis P.
  • Miller, Geoffrey
  • De Jonghe, Peter
  • Ceulemans, Berten
  • Hannibal, Mark C.
  • Edwards, Matthew
  • Thompson, Elizabeth M.
  • Jacobson, Richard
  • Quinlivan, Ros C. M.
  • Aftimos, Salim
  • Kornberg, Andrew J.
  • North, Kathryn N.
  • Bateman, John F.
  • Lamandé, Shireen R.
subjects:
  • Collagen Diseases -- Genetics
  • Collagen Type VI -- Genetics
  • Genes, Dominant -- Genetics
  • Muscular Diseases -- Genetics
  • Polymorphism, Single Nucleotide -- Genetics
ispartof: Annals of Neurology, October 2007, Vol.62(4), pp.390-405
description: 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. We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly. 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. 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.
language: eng
source:
identifier: ISSN: 0364-5134 ; E-ISSN: 1531-8249 ; DOI: 10.1002/ana.21213
fulltext: fulltext
issn:
  • 0364-5134
  • 03645134
  • 1531-8249
  • 15318249
url: Link


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titleMolecular consequences of dominant Bethlem myopathy collagen VI mutations
creatorBaker, Naomi L. ; Mörgelin, Matthias ; Pace, Rishika A. ; Peat, Rachel A. ; Adams, Naomi E. ; Gardner, R. J. Mckinlay ; Rowland, Lewis P. ; Miller, Geoffrey ; De Jonghe, Peter ; Ceulemans, Berten ; Hannibal, Mark C. ; Edwards, Matthew ; Thompson, Elizabeth M. ; Jacobson, Richard ; Quinlivan, Ros C. M. ; Aftimos, Salim ; Kornberg, Andrew J. ; North, Kathryn N. ; Bateman, John F. ; Lamandé, Shireen R.
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descriptionDominant 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. We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly. 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. 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.
subjectCollagen Diseases -- Genetics ; Collagen Type VI -- Genetics ; Genes, Dominant -- Genetics ; Muscular Diseases -- Genetics ; Polymorphism, Single Nucleotide -- Genetics;
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atitleMolecular consequences of dominant Bethlem myopathy collagen VI mutations
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