{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:43:39Z","timestamp":1790516619485,"version":"4.1.0"},"reference-count":73,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T00:00:00Z","timestamp":1616025600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000341","name":"Arthritis Research UK","doi-asserted-by":"publisher","award":["20785"],"award-info":[{"award-number":["20785"]}],"id":[{"id":"10.13039\/501100000341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M009831\/1"],"award-info":[{"award-number":["MR\/M009831\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The human <jats:italic>FBN1<\/jats:italic> gene encodes fibrillin-1 (FBN1); the main component of the 10\u201312 nm diameter extracellular matrix microfibrils. Marfan syndrome (MFS) is a common inherited connective tissue disorder, caused by <jats:italic>FBN1<\/jats:italic> mutations. It features a wide spectrum of disease severity, from mild cases to the lethal neonatal form (nMFS), that is yet to be explained at the molecular level. Mutations associated with nMFS generally affect a region of FBN1 between domains TB3-cbEGF18\u2014the \"neonatal region\". To gain insight into the process of fibril assembly and increase our understanding of the mechanisms determining disease severity in MFS, we compared the secretion and assembly properties of FBN1 variants containing nMFS-associated substitutions with variants associated with milder, classical MFS (cMFS). In the majority of cases, both nMFS- and cMFS-associated neonatal region variants were secreted at levels comparable to wild type. Microfibril incorporation by the nMFS variants was greatly reduced or absent compared to the cMFS forms, however, suggesting that nMFS substitutions disrupt a previously undefined site of microfibril assembly. Additional analysis of a domain deletion variant caused by exon skipping also indicates that register in the neonatal region is likely to be critical for assembly. These data demonstrate for the first time new requirements for microfibril biogenesis and identify at least two distinct molecular mechanisms associated with disease substitutions in the TB3-cbEGF18 region; incorporation of mutant FBN1 into microfibrils changing their integral properties (cMFS) or the blocking of wild type FBN1 assembly by mutant molecules that prevents late-stage lateral assembly (nMFS).<\/jats:p>","DOI":"10.1371\/journal.pone.0248532","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T17:54:02Z","timestamp":1616090042000},"page":"e0248532","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Assembly assay identifies a critical region of human fibrillin-1 required for 10\u201312 nm diameter microfibril biogenesis"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0560-9531","authenticated-orcid":true,"given":"Sacha A.","family":"Jensen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ondine","family":"Atwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penny A.","family":"Handford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"issue":"4","key":"pone.0248532.ref001","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/S0369-8114(01)00147-X","article-title":"Function-structure relationship of elastic arteries in evolution: from microfibrils to elastin and elastic fibres","volume":"49","author":"G Faury","year":"2001","journal-title":"Pathol Biol (Paris)"},{"issue":"36","key":"pone.0248532.ref002","doi-asserted-by":"crossref","first-page":"34605","DOI":"10.1074\/jbc.M303159200","article-title":"Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by alpha 5 beta 1 and alpha v beta 3 integrins","volume":"278","author":"DV Bax","year":"2003","journal-title":"The Journal of biological chemistry"},{"issue":"9","key":"pone.0248532.ref003","first-page":"6743","article-title":"alphaVbeta6 is a novel receptor for human fibrillin-1. 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