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To identify genetic contributions to this phenotypic variability, we performed whole-genome sequencing on four siblings possessing the same\n            <jats:italic>LMNA<\/jats:italic>\n            mutation with differing degrees of skeletal muscle disease severity. We identified a variant in\n            <jats:italic>SMAD7<\/jats:italic>\n            that segregated with severe muscle disease. To functionally test the\n            <jats:italic>SMAD7<\/jats:italic>\n            variant, we generated a\n            <jats:italic>Drosophila<\/jats:italic>\n            model possessing the\n            <jats:italic>LMNA<\/jats:italic>\n            mutation and the\n            <jats:italic>SMAD7<\/jats:italic>\n            variant in the orthologous fly genes. The\n            <jats:italic>SMAD7<\/jats:italic>\n            variant increased SMAD signaling and enhanced muscle defects caused by the mutant lamin. Conversely, overexpression of wild-type\n            <jats:italic>SMAD7<\/jats:italic>\n            rescued muscle function. These findings were extended to humans by showing that SMAD signaling is increased in muscle biopsy tissue from individuals with\n            <jats:italic>LMNA<\/jats:italic>\n            -MD compared to age-matched controls. Collectively, our findings support\n            <jats:italic>SMAD7<\/jats:italic>\n            as the first functionally tested genetic modifier for\n            <jats:italic>LMNA<\/jats:italic>\n            -MD and suggest components of the SMAD pathway as therapeutic targets.\n          <\/jats:p>","DOI":"10.1126\/sciadv.ads7903","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T17:58:46Z","timestamp":1744999126000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["A genetic variant in\n            <i>SMAD7<\/i>\n            acts as a modifier of\n            <i>LMNA<\/i>\n            -associated muscular dystrophy, implicating SMAD signaling as a therapeutic target"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1990-4600","authenticated-orcid":true,"given":"Nathaniel P.","family":"Mohar","sequence":"first","affiliation":[{"name":"Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA."},{"name":"Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6511-1645","authenticated-orcid":true,"given":"Christopher J.","family":"Langland","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4300-7694","authenticated-orcid":true,"given":"Zachary","family":"Darr","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Viles","sequence":"additional","affiliation":[{"name":"Independent researcher, Gowrie, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9279-356X","authenticated-orcid":true,"given":"Benjamin W.","family":"Darbro","sequence":"additional","affiliation":[{"name":"Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA."},{"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4391-7199","authenticated-orcid":true,"given":"Lori L.","family":"Wallrath","sequence":"additional","affiliation":[{"name":"Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA."},{"name":"Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101123"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes11030239"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a000760"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.2999"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2007.03.028"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20110670"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2011-12-5-222"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2020.06.017"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1080\/19491034.2017.1337622"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2023.102313"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/ar.a.20334"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-397920-9.00006-8"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060614-034115"},{"key":"e_1_3_2_15_2","first-page":"11709","article-title":"Lamin A\/C promotes DNA base excision repair","volume":"47","author":"Maynard S.","year":"2019","unstructured":"S. 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