title: Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia.
authors.forename: Rishika A
authors.initials: RA
authors.lastname: Pace
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Peat
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Baker
authors.forename: Laura
authors.initials: L
authors.lastname: Zamurs
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Melita
authors.initials: M
authors.lastname: Irving
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Adams
authors.forename: John F
authors.initials: JF
authors.lastname: Bateman
authors.forename: David
authors.initials: D
authors.lastname: Mowat
authors.forename: Nicholas J C
authors.initials: NJ
authors.lastname: Smith
authors.forename: Phillipa J
authors.initials: PJ
authors.lastname: Lamont
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Mathews
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Shireen R
authors.initials: SR
authors.lastname: Lamandé
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D002478:Cells, Cultured; D003095:Collagen Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D024142:Collagen Type VI / Q000096:biosynthesis / Q000235:genetics*; D003238:Connective Tissue / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005998:Glycine / Q000235:genetics*; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D024142:Collagen Type VI; D012333:RNA, Messenger; D005998:Glycine