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Papers In Press, published online ahead of print November 13, 2001
Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052
Corresponding Author: lamandes{at}cryptic.rch.unimelb.edu.au
Mutations in the genes that code for collagen VI subunits, COL6A1, COL6A2 and COL6A3, are the cause of the dominantly inherited disorder, Bethlem myopathy. Glycine mutations that interrupt the Gly-X-Y repetitive amino acid sequence that forms the characteristic collagen triple helix have been defined in four families, however, the effects of these mutations on collagen VI biosynthesis, assembly, and structure have not been determined. In this study, we examined the consequences of Bethlem myopathy triple helical glycine mutations in the
J. Biol. Chem, 10.1074/jbc.M109932200
Submitted on October 15, 2001
Revised on November 13, 2001
Accepted on November 13, 2001
Kinked collagen VI tetramers and reduced microfibril formation as a result of Bethlem myopathy and introduced triple helical glycine mutations
1(VI) and 2(VI) chains, as well as engineered 3(VI) triple helical glycine mutations. While the Bethlem myopathy and introduced mutations that are towards the N-terminus of the triple helix did not measurably affect collagen VI intracellular monomer, dimer or tetramer assembly, or secretion, the introduced mutation towards the C-terminus of the helix severely impaired association of the mutant 3(VI) chain with 1(VI) and 2(VI). Association of the three chains was not completely prevented, however, and some non-disulfide bonded tetramers were secreted. Examination of the secreted Bethlem myopathy and engineered mutant collagen VI by negative staining electron microscopy revealed the striking finding that in all the cell lines a significant proportion of the tetramers contained a kink in the supercoiled triple helical region. Collagen VI tetramers from all of the mutant cell lines also showed a reduced ability to form microfibrils. These results provide the first evidence of the biosynthetic consequences of collagen VI triple helical glycine mutations, and indicate that Bethlem myopathy results not only from the synthesis of reduced amounts of structurally-normal protein, but also from the presence of mutant collagen VI in the extracellular matrix.
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