title: The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene.
abstract: Systemic sclerosis (SSc) is a polygenic, autoimmune disorder of unknown etiology, characterized by the excessive accumulation of extracellular matrix (ECM) proteins, vascular alterations, and autoantibodies. The tight skin (Tsk)2/+ mouse model of SSc demonstrates signs similar to SSc including tight skin and excessive deposition of dermal ECM proteins. By linkage analysis, we mapped the Tsk2 gene mutation to <3 megabases on chromosome 1. We performed both RNA sequencing of skin transcripts and genome capture DNA sequencing of the region spanning this interval in Tsk2/+ and wild-type littermates. A missense point mutation in the procollagen III amino terminal propeptide segment (PIIINP) of collagen, type III, alpha 1 (Col3a1) was found to be the best candidate for Tsk2; hence, both in vivo and in vitro genetic complementation tests were used to prove that this Col3a1 mutation is the Tsk2 gene. All previously documented mutations in the human Col3a1 gene are associated with the Ehlers-Danlos syndrome, a connective tissue disorder that leads to a defect in type III collagen synthesis. To our knowledge, the Tsk2 point mutation is the first documented gain-of-function mutation associated with Col3a1, which leads instead to fibrosis. This discovery provides insight into the mechanism of skin fibrosis manifested by Tsk2/+ mice.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kristen B
authors.initials: KB
authors.lastname: Long
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Burgwin
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Susanna G
authors.initials: SG
authors.lastname: Choe
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Viktor
authors.initials: V
authors.lastname: Martyanov
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Sihem
authors.initials: S
authors.lastname: Sassi-Gaha
authors.affiliation: Center for Genomic Sciences, Pittsburgh, Pennsylvania, USA.
authors.forename: Josh P
authors.initials: JP
authors.lastname: Earl
authors.affiliation: Center for Genomic Sciences, Pittsburgh, Pennsylvania, USA.
authors.forename: Rory A
authors.initials: RA
authors.lastname: Eutsey
authors.affiliation: Center for Genomic Sciences, Pittsburgh, Pennsylvania, USA.
authors.forename: Azad
authors.initials: A
authors.lastname: Ahmed
authors.affiliation: Center for Genomic Sciences, Pittsburgh, Pennsylvania, USA.
authors.forename: Garth D
authors.initials: GD
authors.lastname: Ehrlich
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Carol M
authors.initials: CM
authors.lastname: Artlett
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Blankenhorn
mesh_terms: D000818:Animals; D024061:Collagen Type III / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D008040:Genetic Linkage; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011347:Procollagen / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000473:pathology*; D012867:Skin / Q000473:pathology
chemical_list: D024061:Collagen Type III; D010446:Peptide Fragments; D011347:Procollagen; C475220:Tsk2 protein, mouse; C041876:procollagen Type III-N-terminal peptide; D017346:Protein Serine-Threonine Kinases