title: Molecular consequences of dominant Bethlem myopathy collagen VI mutations.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
authors: Naomi L
authors: NL
authors: Baker
authors: Matthias
authors: M
authors: Mörgelin
authors: Rishika A
authors: RA
authors: Pace
authors: Rachel A
authors: RA
authors: Peat
authors: Naomi E
authors: NE
authors: Adams
authors: R J McKinlay
authors: RJ
authors: Gardner
authors: Lewis P
authors: LP
authors: Rowland
authors: Geoffrey
authors: G
authors: Miller
authors: Peter
authors: P
authors: De Jonghe
authors: Berten
authors: B
authors: Ceulemans
authors: Mark C
authors: MC
authors: Hannibal
authors: Matthew
authors: M
authors: Edwards
authors: Elizabeth M
authors: EM
authors: Thompson
authors: Richard
authors: R
authors: Jacobson
authors: Ros C M
authors: RC
authors: Quinlivan
authors: Salim
authors: S
authors: Aftimos
authors: Andrew J
authors: AJ
authors: Kornberg
authors: Kathryn N
authors: KN
authors: North
authors: John F
authors: JF
authors: Bateman
authors: Shireen R
authors: SR
authors: Lamandé
mesh_terms: D000328:Adult; D003095:Collagen Diseases / Q000235:genetics*; D024142:Collagen Type VI / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D024142:Collagen Type VI