{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:23:53Z","timestamp":1793381033473,"version":"4.5.0"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"7","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1999,3,30]]},"abstract":"<jats:p>Dissecting aortic aneurysm is the hallmark of Marfan syndrome (MFS) and the result of mutations in fibrillin-1, the major constituent of elastin-associated extracellular microfibrils. It is yet to be established whether dysfunction of fibrillin-1 perturbs the ability of the elastic vessel wall to sustain hemodynamic stress by disrupting microfibrillar assembly, by impairing the homeostasis of established elastic fibers, or by a combination of both mechanisms. The pathogenic sequence responsible for the mechanical collapse of the elastic lamellae in the aortic wall is also unknown. Targeted mutation of the mouse fibrillin-1 gene has recently suggested that deficiency of fibrillin-1 reduces tissue homeostasis rather than elastic fiber formation. Here we describe another gene-targeting mutation, mgR, which shows that underexpression of fibrillin-1 similarly leads to MFS-like manifestations. Histopathological analysis of mgR\/mgR specimens implicates medial calcification, the inflammatory\u2013fibroproliferative response, and inflammation-mediated elastolysis in the natural history of dissecting aneurysm. More generally, the phenotypic severity associated with various combinations of normal and mutant fibrillin-1 alleles suggests a threshold phenomenon for the functional collapse of the vessel wall that is based on the level and the integrity of microfibrils.<\/jats:p>","DOI":"10.1073\/pnas.96.7.3819","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:39:15Z","timestamp":1027679955000},"page":"3819-3823","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":477,"title":["Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1"],"prefix":"10.1073","volume":"96","author":[{"given":"Lygia","family":"Pereira","sequence":"first","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sui Ying","family":"Lee","sequence":"additional","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Gayraud","sequence":"additional","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kostantinos","family":"Andrikopoulos","sequence":"additional","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven D.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracie","family":"Bunton","sequence":"additional","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy Jensen","family":"Biery","sequence":"additional","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry C.","family":"Dietz","sequence":"additional","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn Y.","family":"Sakai","sequence":"additional","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; Istituto de Biociencias, Departamento de Biologia, University of S\u00e3o Paulo, SP 05508 Brazil; Departments of Pediatrics, Medicine, and Cell Biology and Physiology, Washington University School of Medicine at Barnes\u2013Jewish Hospital, St. Louis, MO 63110; Departments of Comparative Medicine and Pathology and Departments of Pediatrics, Medicine, and Molecular Biology..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1999,3,30]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-775170-2.50014-7"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-9062-7_4"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/4.suppl_1.1799"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(96)80007-4"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1097-218"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90611-F"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0195-31"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.18.8424"},{"key":"e_1_3_3_9_2","volume-title":"Molecular Cloning: A Laboratory Manual","author":"Sambrook E","year":"1989","unstructured":"E Sambrook, E F Fritsch, T Maniatis Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Lab. 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