title: COL6A3 protein deficiency in mice leads to muscle and tendon defects similar to human collagen VI congenital muscular dystrophy.
abstract: Collagen VI is a ubiquitously expressed extracellular microfibrillar protein. Its most common molecular form is composed of the α1(VI), α2(VI), and α3(VI) collagen α chains encoded by the COL6A1, COL6A2, and COL6A3 genes, respectively. Mutations in any of the three collagen VI genes cause congenital muscular dystrophy types Bethlem and Ullrich as well as intermediate phenotypes characterized by muscle weakness and connective tissue abnormalities. The α3(VI) collagen α chain has much larger N- and C-globular domains than the other two chains. Its most C-terminal domain can be cleaved off after assembly into microfibrils, and the cleavage product has been implicated in tumor angiogenesis and progression. Here we characterize a Col6a3 mutant mouse that expresses a very low level of a non-functional α3(VI) collagen chain. The mutant mice are deficient in extracellular collagen VI microfibrils and exhibit myopathic features, including decreased muscle mass and contractile force. Ultrastructurally abnormal collagen fibrils were observed in tendon, but not cornea, of the mutant mice, indicating a distinct tissue-specific effect of collagen VI on collagen I fibrillogenesis. Overall, the mice lacking normal α3(VI) collagen chains displayed mild musculoskeletal phenotypes similar to mice deficient in the α1(VI) collagen α chain, suggesting that the cleavage product of the α3(VI) collagen does not elicit essential functions in normal growth and development. The Col6a3 mouse mutant lacking functional α3(VI) collagen chains thus serves as an animal model for COL6A3-related muscular dystrophy.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Te-Cheng
authors.initials: TC
authors.lastname: Pan
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Rui-Zhu
authors.initials: RZ
authors.lastname: Zhang
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Dessislava
authors.initials: D
authors.lastname: Markova
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Machiko
authors.initials: M
authors.lastname: Arita
authors.affiliation: Departments of Orthopedic Surgery and Physical Medicine and Rehabilitation, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Yejia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.affiliation: Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Tejvir S
authors.initials: TS
authors.lastname: Khurana
authors.affiliation: Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20824.
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612.
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107. Electronic address: mon-li.chu@jefferson.edu.
authors.forename: Mon-Li
authors.initials: ML
authors.lastname: Chu
mesh_terms: D000818:Animals; D024142:Collagen Type VI / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005838:Genotype; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020894:Microfibrils / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D010641:Phenotype; D013710:Tendons / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D024142:Collagen Type VI
keywords: Cornea; Extracellular Matrix; Muscular Dystrophy; Skeletal Muscle; Tendon
references.citation: Exerc Sport Sci Rev. 2012 Jan;40(1):43-9
references.pmid: 21918459
references.citation: Nat Genet. 2003 Dec;35(4):367-71
references.pmid: 14625552
references.citation: Nat Rev Neurol. 2011 Jun 21;7(7):379-90
references.pmid: 21691338
references.citation: Nature. 2002 Nov 28;420(6914):418-21
references.pmid: 12459784
references.citation: Dev Dyn. 2010 Mar;239(3):844-54
references.pmid: 20108350
references.citation: N Engl J Med. 2001 Oct 18;345(16):1167-75
references.pmid: 11642233
references.citation: J Biol Chem. 2008 Apr 18;283(16):10658-70
references.pmid: 18276594
references.citation: Nat Med. 2010 Nov;16(11):1313-20
references.pmid: 21037586
references.citation: Am J Med Genet A. 2005 Jan 30;132A(3):296-301
references.pmid: 15690374
references.citation: J Biol Chem. 1992 Nov 25;267(33):24082-9
references.pmid: 1339440
references.citation: Matrix Biol. 2011 May;30(4):248-57
references.pmid: 21477648
references.citation: Matrix Biol. 2011 Jan;30(1):53-61
references.pmid: 20951202
references.citation: Curr Biol. 1998 May 21;8(11):661-4
references.pmid: 9635194
references.citation: FEBS Lett. 1986 Mar 3;197(1-2):55-8
references.pmid: 3512309
references.citation: Exp Cell Res. 2004 Jul 1;297(1):49-60
references.pmid: 15194424
references.citation: J Biol Chem. 2008 Jul 18;283(29):20170-80
references.pmid: 18400749
references.citation: Hum Mol Genet. 1998 Dec;7(13):2135-40
references.pmid: 9817932
references.citation: Brain. 1999 Apr;122 ( Pt 4):649-55
references.pmid: 10219778
references.citation: EMBO J. 1989 Jul;8(7):1939-46
references.pmid: 2551668
references.citation: J Biol Chem. 1988 Dec 15;263(35):18601-6
references.pmid: 3198591
references.citation: Am J Physiol. 1990 Mar;258(3 Pt 1):C436-42
references.pmid: 2316632
references.citation: Nat Genet. 1998 Feb;18(2):136-41
references.pmid: 9462741
references.citation: Cancer Res. 2004 Feb 1;64(3):817-20
references.pmid: 14871805
references.citation: Am J Med Genet A. 2007 Sep 15;143A(18):2215-9
references.pmid: 17702048
references.citation: Muscle Nerve. 2008 Sep;38(3):1184-91
references.pmid: 18720506
references.citation: J Muscle Res Cell Motil. 1993 Aug;14(4):446-51
references.pmid: 7693747
references.citation: J Biol Chem. 2002 Jan 18;277(3):1949-56
references.pmid: 11707460
references.citation: Muscle Nerve. 2008 Mar;37(3):308-16
references.pmid: 18041051
references.citation: Neuromuscul Disord. 2010 May;20(5):346-54
references.pmid: 20211562
references.citation: Biochem J. 1983 May 1;211(2):303-11
references.pmid: 6307276
references.citation: Neuromuscul Disord. 1999 Jul;9(5):326-9
references.pmid: 10407855
references.citation: Skelet Muscle. 2011 Sep 23;1:30
references.pmid: 21943391
references.citation: Structure. 2003 Sep;11(9):1179-88
references.pmid: 12962636
references.citation: J Biol Chem. 2002 Nov 15;277(46):43557-64
references.pmid: 12218063
references.citation: Am J Hum Genet. 2003 Aug;73(2):355-69
references.pmid: 12840783
references.citation: EMBO J. 1990 Feb;9(2):385-93
references.pmid: 1689238
references.citation: Biochem Biophys Res Commun. 2002 Jan 18;290(2):743-8
references.pmid: 11785962
references.citation: J Clin Invest. 2012 Nov;122(11):4243-56
references.pmid: 23041627
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3710-4
references.pmid: 8475120
references.citation: J Biol Chem. 2009 Mar 27;284(13):8888-97
references.pmid: 19136671
references.citation: Biochem J. 1993 May 1;291 ( Pt 3):787-92
references.pmid: 8489506
references.citation: Eur J Biochem. 1994 Oct 15;225(2):573-80
references.pmid: 7525281
references.citation: Exp Cell Res. 2004 Aug 1;298(1):305-15
references.pmid: 15242785
references.citation: EMBO J. 1992 Dec;11(12):4281-90
references.pmid: 1425570
references.citation: Connect Tissue Res. 2011 Oct;52(5):422-32
references.pmid: 21405982
references.citation: J Biol Chem. 2006 Jun 16;281(24):16607-14
references.pmid: 16613849
references.citation: Eur J Biochem. 1994 Apr 1;221(1):177-85
references.pmid: 8168508