{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T22:45:14Z","timestamp":1770504314837,"version":"3.49.0"},"reference-count":26,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2000,8,7]]},"abstract":"<jats:p>The Tight skin (Tsk) mutation is a duplication of the mouse fibrillin 1 (Fbn1) gene that results in a larger (418 kD) than normal (350 kD) protein; Tsk\/+ mice display increased connective tissue, bone overgrowth, and lung emphysema. Lung emphysema, bone overgrowth, and vascular complications are the distinctive traits of mice with reduced Fbn1 gene expression and of Marfan syndrome (MFS) patients with heterozygous fibrillin 1 mutations. Although Tsk\/+ mice produce equal amounts of the 418- and 350-kD proteins, they exhibit a relatively mild phenotype without the vascular complications that are associated with MFS patients and fibrillin 1\u2013deficient mice. We have used genetic crosses, cell culture assays and Tsk-specific antibodies to reconcile this discrepancy and gain new insights into microfibril assembly. Mice compound heterozygous for the Tsk mutation and hypomorphic Fbn1 alleles displayed both Tsk and MFS traits. Analyses of immunoreactive fibrillin 1 microfibrils using Tsk- and species-specific antibodies revealed that the mutant cell cultures elaborate a less abundant and morphologically different meshwork than control cells. Cocultures of Tsk\/Tsk fibroblasts and human WISH cells that do not assemble fibrillin 1 microfibrils, demonstrated that Tsk fibrillin 1 copolymerizes with wild-type fibrillin 1. Additionally, copolymerization of Tsk fibrillin 1 with wild-type fibrillin 1 rescues the abnormal morphology of the Tsk\/Tsk aggregates. Therefore, the studies suggest that bone and lung abnormalities of Tsk\/+ mice are due to copolymerization of mutant and wild-type molecules into functionally deficient microfibrils. However, vascular complications are not present in these animals because the level of functional microfibrils does not drop below the critical threshold. Indirect in vitro evidence suggests that a potential mechanism for the dominant negative effects of incorporating Tsk fibrillin 1 into microfibrils is increased proteolytic susceptibility conferred by the duplicated Tsk region.<\/jats:p>","DOI":"10.1083\/jcb.150.3.667","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:45:41Z","timestamp":1027701941000},"page":"667-680","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":83,"title":["New Insights into the Assembly of Extracellular Microfibrils from the Analysis of the Fibrillin 1 Mutation in the <i>Tight skin<\/i> Mouse"],"prefix":"10.1083","volume":"150","author":[{"given":"Barbara","family":"Gayraud","sequence":"first","affiliation":[{"name":"aBrookdale Center, Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York University, New York, New York 10029"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas R.","family":"Keene","sequence":"additional","affiliation":[{"name":"bThe Shriners Hospital for Children, Portland, Oregon 97201"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn Y.","family":"Sakai","sequence":"additional","affiliation":[{"name":"bThe Shriners Hospital for Children, Portland, Oregon 97201"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Ramirez","sequence":"additional","affiliation":[{"name":"aBrookdale Center, Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York University, New York, New York 10029"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2000,8,7]]},"reference":[{"key":"2023072902323982100_Andrikopoulosetal1995","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/ng0195-31","article-title":"Targeted mutation in the Col5a2 gene reveals a regulatory role for type V collagen during matrix assembly","volume":"9","author":"Andrikopoulos","year":"1995","journal-title":"Nat. Genet."},{"key":"2023072902323982100_BocchieriandJimenez1990","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0889-857X(21)01046-2","article-title":"Animal models of fibrosis","volume":"16","author":"Bocchieri","year":"1990","journal-title":"Rheum. Dis. Clin. North Am."},{"key":"2023072902323982100_DietzandPyeritz1995","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1093\/hmg\/4.suppl_1.1799","article-title":"Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders","volume":"4","author":"Dietz","year":"1995","journal-title":"Hum. Mol. Genet"},{"key":"2023072902323982100_Dietzetal1994","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/978-1-4757-9062-7_4","article-title":"Marfan syndrome and other microfibrillar diseases","volume":"22","author":"Dietz","year":"1994","journal-title":"Adv. Hum. 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Pathol"},{"key":"2023072902323982100_Jimenezetal1984","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/art.1780270209","article-title":"Scleroderma-like alterations in collagen metabolism occurring in the TSK (tight skin) mouse","volume":"27","author":"Jimenez","year":"1984","journal-title":"Arthritis Rheum"},{"key":"2023072902323982100_Kasturietal1997","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1006\/jaut.1997.0158","article-title":"B-cell deficiency does not abrogate development of cutaneous hyperplasia in mice inheriting the defective fibrillin-1 gene","volume":"10","author":"Kasturi","year":"1997","journal-title":"J. Autoimmunity"},{"key":"2023072902323982100_Keeneetal1991","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1177\/39.1.1983874","article-title":"Human bone contains type III collagen, type VI collagen, and fibrillintype III collagen is present on specific fibers that may mediate attachment of tendons, ligaments, and periosteum to calcified bone cortex","volume":"39","author":"Keene","year":"1991","journal-title":"J. Histochem. Cytochem"},{"key":"2023072902323982100_Kieltyetal1998","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1083\/jcb.140.5.1159","article-title":"The Tight skin mousedemonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils","volume":"140","author":"Kielty","year":"1998","journal-title":"J. Cell Biol"},{"key":"2023072902323982100_Martoranaetal1989","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1164\/ajrccm\/139.1.226","article-title":"A 16-month study of the development of genetic emphysema in tight-skin mice","volume":"139","author":"Martorana","year":"1989","journal-title":"Am. Rev. Resp. Dis."},{"key":"2023072902323982100_MechamandDavies1994","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/B978-0-12-775170-2.50014-7","article-title":"Elastic fiber structure and assembly","volume-title":"Extracellular Matrix Assembly and Structure","author":"Mecham","year":"1994"},{"key":"2023072902323982100_Pereiraetal1997","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/ng1097-218","article-title":"Targeting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome","volume":"17","author":"Pereira","year":"1997","journal-title":"Nat. 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Med."},{"key":"2023072902323982100_Reinhardtetal1996","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1006\/jmbi.1996.0237","article-title":"Fibrillin-1organization in microfibrils and structural properties","volume":"258","author":"Reinhardt","year":"1996","journal-title":"J. Mol. Biol"},{"key":"2023072902323982100_Reinhardtetal1997","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1074\/jbc.272.2.1231","article-title":"Calcium stabilizes fibrillin-1 against proteolytic degradation","volume":"272","author":"Reinhardt","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2023072902323982100_Reinhardtetal2000","doi-asserted-by":"crossref","first-page":"12339","DOI":"10.1074\/jbc.275.16.12339","article-title":"Mutations in calcium-binding EGF modules render fibrillin 1 susceptible to proteolysisa potential disease-causing mechanism in Marfan Syndrome","volume":"275","author":"Reinhardt","year":"2000","journal-title":"J. Biol. Chem"},{"key":"2023072902323982100_Renetal1991","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/1047-8477(91)90062-2","article-title":"An analysis by rotary shadowing of the structure of the mammalian vitreous humor and zonular apparatus","volume":"106","author":"Ren","year":"1991","journal-title":"J. Struct. Biol"},{"key":"2023072902323982100_SakaiandKeene1994","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0076-6879(94)45004-8","article-title":"Fibrillinmonomers and microfibrils","volume":"245","author":"Sakai","year":"1994","journal-title":"Methods Enzymol"},{"key":"2023072902323982100_Sakaietal1986","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1083\/jcb.103.4.1577","article-title":"Type VII collagen is a major structural component of anchoring fibrils","volume":"103","author":"Sakai","year":"1986","journal-title":"J. Cell Biol"},{"key":"2023072902323982100_Sakaietal1991","doi-asserted-by":"crossref","first-page":"14763","DOI":"10.1016\/S0021-9258(18)98752-1","article-title":"Purification and partial characterization of fibrillin, a cysteine-rich structural component of connective tissue microfibrils","volume":"266","author":"Sakai","year":"1991","journal-title":"J. Biol. 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