{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:29:28Z","timestamp":1788348568734,"version":"build-2803163510"},"reference-count":17,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2015,4,5]],"date-time":"2015-04-05T00:00:00Z","timestamp":1428192000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:sec><jats:label\/><jats:p>Vascular Ehlers\u2013Danlos syndrome (vEDS) is a heritable disorder of connective tissue caused by pathological variants in the <jats:italic>COL3A1<\/jats:italic> gene, which encodes the \u03b11 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\u2010propeptide region of <jats:italic>COL3A1<\/jats:italic> includes exons 49\u201352 and has a crucial role in initiating the C\u2010terminal assembly of procollagen monomers in the early stages of collagen biosynthesis. Nineteen <jats:italic>COL3A1<\/jats:italic> variants have previously been reported in these exons, of which four were associated with a severe vEDS phenotype. We identified two novel C\u2010propeptide missense variants; p.Pro1440Leu, p.Arg1432Leu, and a non\u2010stop mutation, c.4400A\u2009&gt;\u2009T, p. (*1467Leuext*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\u2010propeptide domain for other human collagen disorders including <jats:italic>COL1A1<\/jats:italic> and <jats:italic>COL1A2<\/jats:italic> (osteogenesis imperfecta). \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.37081","type":"journal-article","created":{"date-parts":[[2015,4,5]],"date-time":"2015-04-05T07:57:00Z","timestamp":1428220620000},"page":"1763-1772","source":"Crossref","is-referenced-by-count":11,"title":["Clinical, structural, biochemical and X\u2010ray crystallographic correlates of pathogenicity for variants in the C\u2010propeptide region of the <i>COL3A1<\/i> gene"],"prefix":"10.1002","volume":"167","author":[{"given":"Natasha S.","family":"Stembridge","sequence":"first","affiliation":[{"name":"Ehlers\u2013Danlos Syndrome National Diagnostic Service Northwick Park and St. Mark's Hospitals Harrow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony M.","family":"Vandersteen","sequence":"additional","affiliation":[{"name":"Maritime Medical Genetics Service IWKHealth Centre Halifax Nova Scotia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeti","family":"Ghali","sequence":"additional","affiliation":[{"name":"Ehlers\u2013Danlos Syndrome National Diagnostic Service Northwick Park and St. Mark's Hospitals Harrow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Sawle","sequence":"additional","affiliation":[{"name":"Ehlers\u2013Danlos Syndrome National Diagnostic Service Northwick Park and St. Mark's Hospitals Harrow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Nesbitt","sequence":"additional","affiliation":[{"name":"Ehlers\u2013Danlos Syndrome National Diagnostic Service Sheffield Diagnostic Genetics Service Sheffield Children's Hospital Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca C.","family":"Pollitt","sequence":"additional","affiliation":[{"name":"Ehlers\u2013Danlos Syndrome National Diagnostic Service Sheffield Diagnostic Genetics Service Sheffield Children's Hospital Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J. P.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Laboratory Science John Radcliffe Hospital Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Holden","sequence":"additional","affiliation":[{"name":"East Anglia Regional Genetics Service Addenbrooke's Hospital Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Elmslie","sequence":"additional","affiliation":[{"name":"South West Thames Regional Genetics Service St. George's Healthcare NHS Trust London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Henderson","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine International Centre for Life Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J. S.","family":"Hulmes","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte de Recherche 5305 Institut de Biologie et Chimie des Prot\u00e9ines Centre National de la Recherche Scientifique Universit\u00e9 Lyon 1 Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.Michael","family":"Pope","sequence":"additional","affiliation":[{"name":"Ehlers\u2013Danlos Syndrome National Diagnostic Service Northwick Park and St. Mark's Hospitals Harrow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,4,5]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19980428)77:1<31::AID-AJMG8>3.0.CO;2-O"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2389"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2007.12.008"},{"key":"e_1_2_6_5_1","unstructured":"DalgleishR.2014.http:\/\/www.le.ac.uk\/ge\/collagen"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2014.181"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10554-007-9283-z"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.113.000280"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.29.6.375"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.72"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12024-010-9205-6"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.72.4.1314"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1996.tb01143.x"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1086\/324123"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2014.01.070"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12286441"},{"key":"e_1_2_6_17_1","doi-asserted-by":"crossref","first-page":"6226","DOI":"10.1016\/S0021-9258(18)68776-9","article-title":"Ehlers\u2010Danlos syndrome type IV: A multi\u2010exon deletion in one of the two COL3A1 alleles affecting structure, stability, and processing of type III procollagen","volume":"263","author":"Superti\u2010Furga A","year":"1988","journal-title":"J Biol Chem"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22677"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fajmg.a.37081","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.37081","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T11:01:22Z","timestamp":1696590082000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.37081"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,5]]},"references-count":17,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2015,8]]}},"alternative-id":["10.1002\/ajmg.a.37081"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.37081","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,4,5]]}}}