Type III collagen affects dermal and vascular collagen fibrillogenesis and tissue integrity in a mutant Col3a1 transgenic mouse model

  • Matrix Biol. 2018 Sep:70:72-83. doi: 10.1016/j.matbio.2018.03.008.
Sanne D'hondt  1 ,  Brecht Guillemyn  2 ,  Delfien Syx  3 ,  Sofie Symoens  4 ,  Riet De Rycke  5 ,  Leen Vanhoutte  6 ,  Wendy Toussaint  7 ,  Bart N Lambrecht  8 ,  Anne De Paepe  9 ,  Douglas R Keene  10 ,  Yoshihiro Ishikawa  11 ,  Hans Peter Bächinger  12 ,  Sophie Janssens  13 ,  Mathieu J M Bertrand  14 ,  Fransiska Malfait  15
Affiliations
  • 1. Center for Medical Genetics, Ghent University and University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: [email protected].
  • 2. Center for Medical Genetics, Ghent University and University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: [email protected].
  • 3. Center for Medical Genetics, Ghent University and University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: [email protected].
  • 4. Center for Medical Genetics, Ghent University and University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: [email protected].
  • 5. VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium; VIB Center for Plant Systems Biology, Technologiepark 927, 9052 Ghent, Belgium; Department of Plant Biotechnology and Bioinformatics, Ghent University, Technologiepark 927, 9052 Ghent, Belgium. Electronic address: [email protected].
  • 6. VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium; Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium. Electronic address: [email protected].
  • 7. VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium; Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium. Electronic address: [email protected].
  • 8. VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium; Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium; GROUP-ID Consortium, Ghent University and University Hospital, De Pindelaan 185, 9000 Ghent, Belgium; Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: [email protected].
  • 9. Center for Medical Genetics, Ghent University and University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: [email protected].
  • 10. Micro-imaging Center, Shriners Hospitals for Children Portland, 3101 SW Sam Jackson Park Rd, Portland, OR 97239, United States. Electronic address: [email protected].
  • 11. Department of Biochemistry and Molecular Biology, Oregon Health & Science University Portland and Shriners Hospitals for Children Portland, 3101 SW Sam Jackson Park Rd, Portland, OR 97239, United States. Electronic address: [email protected].
  • 12. Department of Biochemistry and Molecular Biology, Oregon Health & Science University Portland and Shriners Hospitals for Children Portland, 3101 SW Sam Jackson Park Rd, Portland, OR 97239, United States. Electronic address: [email protected].
  • 13. VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium; Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium; GROUP-ID Consortium, Ghent University and University Hospital, De Pindelaan 185, 9000 Ghent, Belgium; Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: [email protected].
  • 14. VIB Center for Inflammation Research, Technologiepark 927, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium; GROUP-ID Consortium, Ghent University and University Hospital, De Pindelaan 185, 9000 Ghent, Belgium. Electronic address: [email protected].
  • 15. Center for Medical Genetics, Ghent University and University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: [email protected].
PMID: 29551664 DOI: 10.1016/j.matbio.2018.03.008
Abstract

Type III Collagen is a major fibrillar Collagen consisting of three identical α1(III)-chains that is particularly present in tissues exhibiting elastic properties, such as the skin and the arterial wall. Heterozygous mutations in the COL3A1 gene result in vascular Ehlers-Danlos syndrome (vEDS), a severe, life-threatening disorder, characterized by thin, translucent skin and propensity to arterial, intestinal and uterine rupture. Most human vEDS cases result from a missense mutation substituting a crucial glycine residue in the triple helical domain of the α1(III)-chains. The mechanisms by which these mutant type III Collagen molecules cause dermal and vascular fragility are not well understood. We generated a transgenic mouse line expressing mutant type III Collagen, containing a typical helical glycine substitution (p.(Gly182Ser)). This Col3a1Tg-G182S mouse line displays a phenotype recapitulating characteristics of human vEDS patients with signs of dermal and vascular fragility. The Col3a1Tg-G182S mice develop severe transdermal skin wounds, resulting in early demise at 13-14weeks of age. We found that this phenotype was associated with a reduced total Collagen content and an abnormal Collagen III:I ratio, leading to the production of severely malformed Collagen fibrils in the extracellular matrix of dermal and arterial tissues. These results indicate that expression of the glycine substitution in the α1(III)-chain disturbs formation of heterotypic type III:I Collagen fibrils, and thereby demonstrate a key role for type III Collagen in Collagen fibrillogenesis in dermal and arterial tissues.

Keywords
Fibrillogenesis; Heritable connective tissue disorder; Transgenic mouse model; Type III collagen; Vascular Ehlers-Danlos syndrome.