Journal
MATRIX BIOLOGY
Volume 70, Issue -, Pages 72-83Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.matbio.2018.03.008
Keywords
Type III collagen; Vascular Ehlers-Danlos syndrome; Heritable connective tissue disorder; Transgenic mouse model; Fibrillogenesis
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Funding
- Methusalem Grant from the Ghent University [BOFMET 2015000401]
- Flanders Research Foundation [G17212N, G013715N]
- European Research Council
- Ghent University Multidisciplinary Research Platform Grant [GROUP-ID consortium]
- Shriners Hospital for Children [85100, 85500]
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Type Ill collagen is a major fibrillar collagen consisting of three identical alpha(1)(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 alpha(1)(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 Col3a1(Tg-)(G182S) mouse line displays a phenotype recapitulating characteristics of human vEDS patients with signs of dermal and vascular fragility. The Col3a1(Tg-G182S) mice develop severe transdermal skin wounds, resulting in early demise at 13-14 weeks 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 alpha(1)(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. (C) 2018 Elsevier B.V. All rights reserved.
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