title: Collagen VI microfibril formation is abolished by an {alpha}2(VI) von Willebrand factor type A domain mutation in a patient with Ullrich congenital muscular dystrophy.
abstract: Collagen VI is an extracellular protein that most often contains the three genetically distinct polypeptide chains, α1(VI), α2(VI), and α3(VI), although three recently identified chains, α4(VI), α5(VI), and α6(VI), may replace α3(VI) in some situations. Each chain has a triple helix flanked by N- and C-terminal globular domains that share homology with the von Willebrand factor type A (VWA) domains. During biosynthesis, the three chains come together to form triple helical monomers, which then assemble into dimers and tetramers. Tetramers are secreted from the cell and align end-to-end to form microfibrils. The precise molecular mechanisms responsible for assembly are unclear. Mutations in the three collagen VI genes can disrupt collagen VI biosynthesis and matrix organization and are the cause of the inherited disorders Bethlem myopathy and Ullrich congenital muscular dystrophy. We have identified a Ullrich congenital muscular dystrophy patient with compound heterozygous mutations in α2(VI). The first mutation causes skipping of exon 24, and the mRNA is degraded by nonsense-mediated decay. The second mutation is a two-amino acid deletion in the C1 VWA domain. Recombinant C1 domains containing the deletion are insoluble and retained intracellularly, indicating that the mutation has detrimental effects on domain folding and structure. Despite this, mutant α2(VI) chains retain the ability to associate into monomers, dimers, and tetramers. However, we show that secreted mutant tetramers containing structurally abnormal C1 VWA domains are unable to associate further into microfibrils, directly demonstrating the critical importance of a correctly folded α2(VI) C1 domain in microfibril formation.
authors: From the Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia; Departments of Paediatrics, Parkville, Victoria 3052, Australia.
authors: Leona D
authors: LD
authors: Tooley
authors: From the Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors: Laura K
authors: LK
authors: Zamurs
authors: Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, United Kingdom.
authors: Nicola
authors: N
authors: Beecher
authors: From the Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors: Naomi L
authors: NL
authors: Baker
authors: Neurogenetics Research Unit, Children's Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, Westmead, New South Wales 2145, Australia.
authors: Rachel A
authors: RA
authors: Peat
authors: From the Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors: Naomi E
authors: NE
authors: Adams
authors: From the Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia; Biochemistry and Molecular Biology, University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors: John F
authors: JF
authors: Bateman
authors: Neurogenetics Research Unit, Children's Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, Westmead, New South Wales 2145, Australia.
authors: Kathryn N
authors: KN
authors: North
authors: Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, United Kingdom.
authors: Clair
authors: C
authors: Baldock
authors: From the Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia; Departments of Paediatrics, Parkville, Victoria 3052, Australia. Electronic address: shireen.lamande@mcri.edu.au.
authors: Shireen R
authors: SR
authors: Lamandé
mesh_terms: D002460:Cell Line; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D017510:Protein Folding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D024142:Collagen Type VI; D012333:RNA, Messenger; D014841:von Willebrand Factor