{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:00:38Z","timestamp":1788786038243,"version":"build-2803163510"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T00:00:00Z","timestamp":1711497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Erasmus MC Mrace"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Pathogenic (P)\/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Investigate the impact of P\/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A retrospective analysis on clinical data from individuals with a P\/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Individuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P\u00a0=\u20090.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0\u00a0years [IQR 29.0\u201347.0] in individuals with DN variants in MH2, compared to 46.0\u00a0years [IQR 40.0\u201354.0] in those with HI variants (P\u2009=\u20090.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Distinguishing between P\/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/hmg\/ddae044","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T17:21:13Z","timestamp":1709745673000},"page":"1090-1104","source":"Crossref","is-referenced-by-count":4,"title":["Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation"],"prefix":"10.1093","volume":"33","author":[{"given":"Nathalie P","family":"de Wagenaar","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"Department of Cardiology and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN) , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1195-6054","authenticated-orcid":false,"given":"Lisa M","family":"van den Bersselaar","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN) , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanny J H M","family":"Odijk","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne J M","family":"Stefens","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter P","family":"Reinhardt","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, McGill University , 3640 University Street, Montreal, QC H3A 0C7 , Canada"},{"name":"Faculty of Dental Medicine and Oral Health Sciences, McGill University , 3640 University Street, Montreal, QC H3A 0C7 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien W","family":"Roos-Hesselink","sequence":"additional","affiliation":[{"name":"Department of Cardiology and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN) , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Kanaar","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith M A","family":"Verhagen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN) , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hennie T","family":"Br\u00fcggenwirth","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN) , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M B H","family":"van de Laar","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN) , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , HTAD Rare Disease Working Group, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"van der Pluijm","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"Department of Vascular Surgery , Cardiovascular Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , Cardiovascular Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Essers","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , Oncode Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"Department of Vascular Surgery , Cardiovascular Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , Cardiovascular Institute, Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"Department of Radiotherapy , Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"},{"name":"University Medical Center Rotterdam , Erasmus MC, , Dr. Molewaterplein 40, 3015 GD, Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"2024060606012598000_ref1","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1067\/mva.1991.26737","article-title":"Suggested standards for reporting on arterial aneurysms. 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signaling","volume":"347","author":"Heldin","year":"2012","journal-title":"Cell Tissue Res"},{"key":"2024060606012598000_ref20","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1146\/annurev.biochem.67.1.753","article-title":"TGF-beta signal transduction","volume":"67","author":"Massagu\u00e9","year":"1998","journal-title":"Annu Rev Biochem"},{"key":"2024060606012598000_ref21","first-page":"616","article-title":"TGF\u03b2 signalling in context","volume":"13","author":"Massagu\u00e9","year":"2012","journal-title":"Mol Cell Biol"},{"key":"2024060606012598000_ref22","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/nature10145","article-title":"Lessons on the pathogenesis of aneurysm from heritable conditions","volume":"473","author":"Lindsay","year":"2011","journal-title":"Nature"},{"key":"2024060606012598000_ref23","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.tibs.2015.03.012","article-title":"Structural determinants of Smad function in 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Two case reports","volume":"8","author":"Keravnou","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"2024060606012598000_ref26","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3390\/medicina55050137","article-title":"Genomic observations of a rare\/pathogenic SMAD3 variant in Loeys-Dietz syndrome 3 confirmed by protein informatics and structural investigations","volume":"55","author":"Richter","year":"2019","journal-title":"Medicina (Kaunas)"},{"key":"2024060606012598000_ref27","doi-asserted-by":"crossref","first-page":"764","DOI":"10.3390\/genes10100764","article-title":"Genotypic categorization of Loeys-Dietz syndrome based on 24 novel families and literature data","volume":"10","author":"Camerota","year":"2019","journal-title":"Genes (Basel)"},{"key":"2024060606012598000_ref28","doi-asserted-by":"crossref","first-page":"e1089","DOI":"10.1002\/mgg3.1089","article-title":"Novel SMAD3 p.Arg386Thr genetic variant co-segregating with thoracic aortic aneurysm and dissection","volume":"8","author":"Engstr\u00f6m","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"2024060606012598000_ref29","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1002\/humu.23565","article-title":"Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders","volume":"39","author":"Overwater","year":"2018","journal-title":"Hum Mutat"},{"key":"2024060606012598000_ref30","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1399-0004.2012.01931.x","article-title":"An unanticipated copy number variant of chromosome 15 disrupting SMAD3 reveals a three-generation family at serious risk for aortic dissection","volume":"83","author":"Hilhorst-Hofstee","year":"2013","journal-title":"Clin Genet"},{"key":"2024060606012598000_ref31","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1136\/jmedgenet-2018-105583","article-title":"SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino aortic consortium","volume":"56","author":"Hostetler","year":"2019","journal-title":"J Med Genet"},{"key":"2024060606012598000_ref32","doi-asserted-by":"crossref","first-page":"e1132","DOI":"10.1002\/mgg3.1132","article-title":"Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature","volume":"8","author":"Chesneau","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"2024060606012598000_ref33","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3390\/genes11030239","article-title":"Genetic modifiers and rare Mendelian disease","volume":"11","author":"Rahit","year":"2020","journal-title":"Genes (Basel)"},{"key":"2024060606012598000_ref34","doi-asserted-by":"crossref","first-page":"e334","DOI":"10.1161\/CIR.0000000000001106","article-title":"2022 ACC\/AHA guideline for the diagnosis and Management of Aortic Disease: a report of the American Heart Association\/American College of Cardiology Joint Committee on clinical practice guidelines","volume":"146","author":"Isselbacher","year":"2022","journal-title":"Circulation"},{"key":"2024060606012598000_ref35","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1002\/1097-0029(20000915)50:6<532::AID-JEMT10>3.0.CO;2-E","article-title":"Smooth muscle myosin heavy chain isoforms and their role in muscle physiology","volume":"50","author":"Babu","year":"2000","journal-title":"Microsc Res Tech"},{"key":"2024060606012598000_ref36","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1093\/hmg\/ddab190","article-title":"Molecular phenotyping and functional assessment of smooth muscle like-cells with pathogenic variants in aneurysm genes ACTA2, MYH11, SMAD3 and FBN1","volume":"30","author":"Burger","year":"2021","journal-title":"Hum Mol Genet"},{"key":"2024060606012598000_ref37","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.ebiom.2016.09.006","article-title":"Defective connective tissue Remodeling in Smad3 mice leads to accelerated aneurysmal growth through disturbed downstream TGF-beta Signaling","volume":"12","author":"Pluijm","year":"2016","journal-title":"EBioMedicine"},{"key":"2024060606012598000_ref38","doi-asserted-by":"crossref","first-page":"118703","DOI":"10.1016\/j.bbamcr.2020.118703","article-title":"The role of Smad2 and Smad3 in regulating homeostatic functions of fibroblasts in vitro and in adult mice","volume":"1867","author":"Huang","year":"2020","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"2024060606012598000_ref39","doi-asserted-by":"crossref","first-page":"826495","DOI":"10.3389\/fcvm.2022.826495","article-title":"Postnatal Smad3 inactivation in murine smooth muscle cells elicits a temporally and regionally distinct transcriptional response","volume":"9","author":"Bramel","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"2024060606012598000_ref40","doi-asserted-by":"crossref","first-page":"dev200298","DOI":"10.1242\/dev.200298","article-title":"The origins of skin diversity: lessons from dermal fibroblasts","volume":"149","author":"Myung","year":"2022","journal-title":"Development"},{"key":"2024060606012598000_ref41","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.yjmcc.2014.01.016","article-title":"Embryonic domains of the aorta derived from diverse origins exhibit distinct properties that converge into a common phenotype in the adult","volume":"69","author":"Pfaltzgraff","year":"2014","journal-title":"J Mol Cell Cardiol"},{"key":"2024060606012598000_ref42","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/nbt.2107","article-title":"Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility","volume":"30","author":"Cheung","year":"2012","journal-title":"Nat Biotechnol"},{"key":"2024060606012598000_ref43","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1096\/fj.11-185454","article-title":"Origin-specific epigenetic program correlates with vascular bed-specific differences in Rgs5 expression","volume":"26","author":"Zhang","year":"2012","journal-title":"FASEB J"},{"key":"2024060606012598000_ref44","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/0021-9150(71)90080-3","article-title":"Experimental canine atherosclerosis in autogenous abdominal aortic grafts implanted into the jugular vein","volume":"13","author":"Haimovici","year":"1971","journal-title":"Atherosclerosis"},{"key":"2024060606012598000_ref45","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1152\/physrev.00003.2017","article-title":"Vascular smooth muscle cells and arterial stiffening: relevance in development, aging, and 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Biol"},{"key":"2024060606012598000_ref49","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s10741-007-9034-1","article-title":"Return to the fetal gene program protects the stressed heart: a strong hypothesis","volume":"12","author":"Rajabi","year":"2007","journal-title":"Heart Fail Rev"},{"key":"2024060606012598000_ref50","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. 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