title: A mouse model for dominant collagen VI disorders: heterozygous deletion of Col6a3 Exon 16.
abstract: Dominant and recessive mutations in collagen VI genes, COL6A1, COL6A2, and COL6A3, cause a continuous spectrum of disorders characterized by muscle weakness and connective tissue abnormalities ranging from the severe Ullrich congenital muscular dystrophy to the mild Bethlem myopathy. Herein, we report the development of a mouse model for dominant collagen VI disorders by deleting exon 16 in the Col6a3 gene. The resulting heterozygous mouse, Col6a3(+/d16), produced comparable amounts of normal Col6a3 mRNA and a mutant transcript with an in-frame deletion of 54 bp of triple-helical coding sequences, thus mimicking the most common molecular defect found in dominant Ullrich congenital muscular dystrophy patients. Biosynthetic studies of mutant fibroblasts indicated that the mutant α3(VI) collagen protein was produced and exerted a dominant-negative effect on collagen VI microfibrillar assembly. The distribution of the α3(VI)-like chains of collagen VI was not altered in mutant mice during development. The Col6a3(+/d16) mice developed histopathologic signs of myopathy and showed ultrastructural alterations of mitochondria and sarcoplasmic reticulum in muscle and abnormal collagen fibrils in tendons. The Col6a3(+/d16) mice displayed compromised muscle contractile functions and thereby provide an essential preclinical platform for developing treatment strategies for dominant collagen VI disorders.
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: Machiko
authors.initials: M
authors.lastname: Arita
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 Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, Florida 33612.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Adams
authors.affiliation: Center for Biochemistry, Medical Faculty Cologne, University of Cologne, Cologne D-50931, Germany.
authors.forename: Sudheer Kumar
authors.initials: SK
authors.lastname: Gara
authors.affiliation: Center for Biochemistry, Medical Faculty Cologne, University of Cologne, Cologne D-50931, Germany; Center for Molecular Medicine, Medical Faculty Cologne, University of Cologne, Cologne D-50931, Germany.
authors.forename: Raimund
authors.initials: R
authors.lastname: Wagener
authors.affiliation: Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Tejvior S
authors.initials: TS
authors.lastname: Khurana
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, 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: D000483:Alleles; D000818:Animals; D024142:Collagen Type VI / Q000737:chemistry* / Q000235:genetics*; D004195:Disease Models, Animal; D005091:Exons; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005799:Genes, Dominant; D006579:Heterozygote; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D009119:Muscle Contraction; D009132:Muscles / Q000503:physiopathology; D009135:Muscular Diseases / Q000235:genetics / Q000503:physiopathology*; D009136:Muscular Dystrophies / Q000235:genetics; D010641:Phenotype; D012519:Sarcoplasmic Reticulum / Q000473:pathology; D017384:Sequence Deletion; D013710:Tendons / Q000473:pathology
chemical_list: D024142:Collagen Type VI
keywords: Connective Tissue; Extracellular Matrix; Fibroblast; Muscle; Tendon