{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:15:05Z","timestamp":1790255705889,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T00:00:00Z","timestamp":1697760000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Loeys\u2013Dietz syndrome (LDS) is a heritable disorder of connective tissue closely related to Marfan syndrome (MFS). LDS is caused by loss\u2010of\u2010function variants of genes that encode components of transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2) signaling; nevertheless, LDS type 1\/2 caused by <jats:italic>TGFBR1\/2<\/jats:italic> pathogenic variants is frequently found to have paradoxical increases in TGF\u2010\u03b2 signaling in the aneurysmal aortic wall. Here, we present a Japanese LDS family having a novel <jats:italic>SMAD3<\/jats:italic> variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The proband was tested via clinical, genetic, and histological analyses. In vitro analysis was performed for pathogenic evaluation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The novel heterozygous missense variant of <jats:italic>SMAD3<\/jats:italic> [c.1262G&gt;A, p.(Cys421Tyr)], located just upstream of the C\u2010terminal Ser423\u2010X\u2010Ser425 phosphorylation motif, was found in this instance of LDS type 3. This variant led to reduced phospho\u2010SMAD3 (Ser423\/Ser425) levels and transcription activity in vitro; however, a paradoxical upregulation of TGF\u2010\u03b2 signaling was evident in the aortic wall.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results revealed the presence of TGF\u2010\u03b2 paradox in this case with the novel loss\u2010of\u2010function <jats:italic>SMAD3<\/jats:italic> variant. The precise mechanism underlying the paradox is unknown, but further research is warranted to clarify the influence of the <jats:italic>SMAD3<\/jats:italic> variant type and location on the LDS3 phenotype as well as the molecular mechanism leading to LDS3 aortopathy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2257","type":"journal-article","created":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T04:51:16Z","timestamp":1697863876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A novel pathogenic variant located just upstream of the <scp>C<\/scp>\u2010terminal Ser423\u2010X\u2010Ser425 phosphorylation motif in <i>SMAD3<\/i> causing Loeys\u2013Dietz syndrome"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0858-9150","authenticated-orcid":false,"given":"Satoshi","family":"Ishii","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine The 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