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Vascular Ehlers-Danlos syndrome (vEDS) is a heritable disorder of connective tissue caused by pathological variants in the COL3A1 gene, which encodes the alpha 1 chain of type III collagen. Type III collagen is a major component of skin, arterial walls, and the gastrointestinal tract. Collagen III protein deficiency manifests as an increased risk of rupture, perforation, and dissection of these structures. The most disruptive gene variants affect the collagen helix via glycine substitutions or splice donor site mutations. The C-propeptide region of COL3A1 includes exons 49-52 and has a crucial role in initiating the C-terminal assembly of procollagen monomers in the early stages of collagen biosynthesis. Nineteen COL3A1 variants have previously been reported in these exons, of which four were associated with a severe vEDS phenotype. We identified two novel C-propeptide missense variants; p.Pro1440Leu, p. Arg1432Leu, and a non-stop mutation, c.4400A > T, p. ((star)1467Leuext(star) 45). These variants produce variable phenotypes ranging from obvious acrogeria to classical or hypermobile EDS. A previously reported variant p.Lys1313Arg is of unknown clinical significance but likely benign, based on this study. Assigning disease pathogenicity remains complex, clinical phenotyping and crystal structure evidence being crucial. We briefly compare reported phenotypes for patients with missense variants in the C-propeptide domain for other human collagen disorders including COL1A1 and COL1A2 (osteogenesis imperfecta). (C) 2015 Wiley Periodicals, Inc.
Author(s): Stembridge NS, Vandersteen AM, Ghali N, Sawle P, Nesbitt M, Pollitt RC, Ferguson DJP, Holden S, Elmslie F, Henderson A, Hulmes DJS, Pope FM
Publication type: Article
Publication status: Published
Journal: American Journal of Medical Genetics Part A
Year: 2015
Volume: 167
Issue: 8
Pages: 1763-1772
Print publication date: 01/08/2015
Online publication date: 05/04/2015
Acceptance date: 12/03/2015
ISSN (print): 1552-4825
ISSN (electronic): 1552-4833
Publisher: Wiley-Blackwell Publishing Ltd.
URL: http://dx.doi.org/10.1002/ajmg.a.37081
DOI: 10.1002/ajmg.a.37081
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