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J. Biol. Chem., Vol. 277, Issue 3, 1949-1956, January 18, 2002

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Kinked Collagen VI Tetramers and Reduced Microfibril Formation as a Result of Bethlem Myopathy and Introduced Triple Helical Glycine Mutations^*

Shireen R. Lamandé^§, Matthias Mörgelin^¶, Carly Selan, G. Joost Jöbsis, Frank Baas, and John F. Bateman

From the  Cell and Matrix Biology Research Unit, Department of Paediatrics, University of Melbourne, the Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia, the ^¶ Department of Cell and Molecular Biology, Lund University, BMC, C12 221 84 Lund, Sweden, and the  Department of Neurology, Academic Medical Center, P. O. Box 22700, 1100 DE Amsterdam, The Netherlands

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 1(VI) and 2(VI) chains, as well as engineered 3(VI) triple helical glycine mutations. Although the Bethlem myopathy and introduced mutations that are toward the N terminus of the triple helix did not measurably affect collagen VI intracellular monomer, dimer, or tetramer assembly, or secretion, the introduced mutation toward 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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