{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:17:19Z","timestamp":1789471039794,"version":"build-2803163510"},"reference-count":20,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2019,7,27]],"date-time":"2019-07-27T00:00:00Z","timestamp":1564185600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Geleophysic dysplasia (GPHYSD) is a disorder characterized by dysmorphic features, stiff joints and cardiac involvement due to defects of TGF\u2010\u03b2 signaling. GPHYSD can be caused by mutations in <jats:italic>FBN1<\/jats:italic>, <jats:italic>ADAMTLS2<\/jats:italic>, and <jats:italic>LTBP3<\/jats:italic> genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Consistent with previous reports, we found intracellular inclusions of unknown material by electron microscopy (EM) in skin fibroblasts of two GPHYSD individuals carrying <jats:italic>FBN1<\/jats:italic> mutations. Moreover, we found that the storage material is enclosed within lysosomes and is associated with the upregulation of several lysosomal genes. Treatment of GPHYSD fibroblasts carrying <jats:italic>FBN1<\/jats:italic> mutations with the angiotensin II receptor type 1 inhibitor losartan that inhibits TGF\u2010\u03b2 signaling did not reduce the storage but improved the extracellular deposition of fibrillin\u20101 microfibrils.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Losartan is a promising candidate drug for treatment of GPHYSD due to <jats:italic>FBN1<\/jats:italic> defects.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.844","type":"journal-article","created":{"date-parts":[[2019,7,27]],"date-time":"2019-07-27T08:40:37Z","timestamp":1564216837000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Skin fibroblasts of patients with geleophysic dysplasia due to <i>FBN1<\/i> mutations have lysosomal inclusions and losartan improves their microfibril deposition defect"],"prefix":"10.1002","volume":"7","author":[{"given":"Pasquale","family":"Piccolo","sequence":"first","affiliation":[{"name":"Telethon Institute of Genetics and Medicine Pozzuoli Italy"},{"name":"Department of Translational Medicine Federico II University of Naples Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Sabatino","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratibha","family":"Mithbaokar","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Polishchuk","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hicks","sequence":"additional","affiliation":[{"name":"Department of Pathology Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Polishchuk","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos A.","family":"Bacino","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6895-8819","authenticated-orcid":false,"given":"Nicola","family":"Brunetti\u2010Pierri","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine Pozzuoli Italy"},{"name":"Department of Translational Medicine Federico II University of Naples Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0706585"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.12.011"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2012.05.027"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.40.1.34"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.017046"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1016"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.05.012"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.199"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320280522"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3000488"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1994.1110"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2015-103647"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2013.283"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-417164-0.00015-X"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.039669"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320580304"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(71)92073-3"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-013-2290-0"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.21.1.80"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320350202"}],"container-title":["Molecular Genetics &amp; 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