A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression
Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within an...
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| creator | Lima, Bruno L Santos, Enrico J C Fernandes, Gustavo R Merkel, Christian Mello, Marco R B Gomes, Juliana P A Soukoyan, Marina Kerkis, Alexandre Massironi, Silvia M G Visintin, José A Pereira, Lygia V |
| description | Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19-24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression. |
| doi_str_mv | 10.1371/journal.pone.0014136 |
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Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19-24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0014136</identifier><identifier>PMID: 21152435</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Animals ; Aorta ; Base Sequence ; Bone diseases ; Cardiovascular Disorders/Vascular Biology ; Cells, Cultured ; Connective tissues ; Deoxyribonucleic acid ; Disease ; Disease Models, Animal ; DNA ; Embryo, Mammalian - cytology ; Embryo, Mammalian - metabolism ; Emphysema ; Epigenetics ; Exons ; Fibrillin ; Fibrillin-1 ; Fibrillins ; Fibroblasts - cytology ; Fibroblasts - metabolism ; Fluorescent Antibody Technique ; Gene Expression ; Genetic aspects ; Genetic disorders ; Genetic variability ; Genetics ; Genetics and Genomics ; Genetics and Genomics/Disease Models ; Genetics and Genomics/Epigenetics ; Genetics and Genomics/Gene Expression ; Genotype ; Heterogeneity ; Heterozygotes ; Humans ; Kyphosis ; Laboratories ; Marfan syndrome ; Marfan Syndrome - genetics ; Marfan Syndrome - metabolism ; Marfan Syndrome - pathology ; Marfan's syndrome ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Microfilament Proteins - genetics ; Microfilament Proteins - metabolism ; Mutation ; Pathogenesis ; Personal computers ; Phenotype ; Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; Stem cells ; Trends ; Variability</subject><ispartof>PloS one, 2010-11, Vol.5 (11), p.e14136-e14136</ispartof><rights>COPYRIGHT 2010 Public Library of Science</rights><rights>2010 Lima et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19-24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. 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metabolism</subject><subject>Mutation</subject><subject>Pathogenesis</subject><subject>Personal computers</subject><subject>Phenotype</subject><subject>Proteins</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Stem cells</subject><subject>Trends</subject><subject>Variability</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11rFDEUhgdRbK3-A9GAoHix6ySZmUxuhKVYLRQKft2GTOZkN2s2WZPMtvs3_MVm7LbsSkEZ5oPMc96c856coniOyymmDL9b-iE4aadr72BalrjCtHlQHGNOyaQhJX24931UPIlxWZY1bZvmcXFEMK5JRevj4tcMObhCKz9EyM8eLNI-oJUMWjoUt64PfgVoHSCCSxGtF-B82q6NQhsZjOyMNWmLZIxeGZmgR1cmLVBaAJqDg5S5Tqof8-AH1yOZb7-BIK1FFjZgI_IanXUOI7ge94jGu6fFIy1thGe790nx7ezD19NPk4vLj-ens4uJYoSmCaes4arqMNFN25cKS6Z1XbbAal7zXKesZE0ZqThva9lRprnGvNZUkQYaielJ8fJGd219FDs7o8CEk6qhNRmJ8xui93Ip1sFkW7bCSyP-LPgwFzLkEi0IwhVXuq0kyznJRvK6IV1OEauyqVQ7ar3f7TZ0K-hVdjPbcCB6-MeZhZj7TVbmFSNtFnizEwj-5wAxiZWJCqyVDnL3RNuUtKUVL_9NkpK1LWFjUq_-Iu-3YUfNZa7UOO1zgmrUFLOK0ZZwxlmmpvdQ-ephZVQ-pNrk9YOAtwcBmUlwneZyiFGcf_n8_-zl90P29R67AGnTIno7pHy24iFY3YAq-BgD6Ltu4FKMM3brhhhnTOxmLIe92O_kXdDtUNHfNR8irw</recordid><startdate>20101130</startdate><enddate>20101130</enddate><creator>Lima, Bruno L</creator><creator>Santos, Enrico J C</creator><creator>Fernandes, Gustavo R</creator><creator>Merkel, Christian</creator><creator>Mello, Marco R B</creator><creator>Gomes, Juliana P A</creator><creator>Soukoyan, Marina</creator><creator>Kerkis, Alexandre</creator><creator>Massironi, Silvia M G</creator><creator>Visintin, José A</creator><creator>Pereira, Lygia V</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20101130</creationdate><title>A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression</title><author>Lima, Bruno L ; Santos, Enrico J C ; Fernandes, Gustavo R ; Merkel, Christian ; Mello, Marco R B ; Gomes, Juliana P A ; Soukoyan, Marina ; Kerkis, Alexandre ; Massironi, Silvia M G ; Visintin, José A ; Pereira, Lygia V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c723t-93769c4b12f68d0c1a7ff508e75959866a4a537249985ab37f9f195f3c26e6a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Analysis</topic><topic>Animals</topic><topic>Aorta</topic><topic>Base Sequence</topic><topic>Bone diseases</topic><topic>Cardiovascular Disorders/Vascular Biology</topic><topic>Cells, Cultured</topic><topic>Connective tissues</topic><topic>Deoxyribonucleic acid</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>DNA</topic><topic>Embryo, Mammalian - 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Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19-24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21152435</pmid><doi>10.1371/journal.pone.0014136</doi><tpages>e14136</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1292463521 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Analysis Animals Aorta Base Sequence Bone diseases Cardiovascular Disorders/Vascular Biology Cells, Cultured Connective tissues Deoxyribonucleic acid Disease Disease Models, Animal DNA Embryo, Mammalian - cytology Embryo, Mammalian - metabolism Emphysema Epigenetics Exons Fibrillin Fibrillin-1 Fibrillins Fibroblasts - cytology Fibroblasts - metabolism Fluorescent Antibody Technique Gene Expression Genetic aspects Genetic disorders Genetic variability Genetics Genetics and Genomics Genetics and Genomics/Disease Models Genetics and Genomics/Epigenetics Genetics and Genomics/Gene Expression Genotype Heterogeneity Heterozygotes Humans Kyphosis Laboratories Marfan syndrome Marfan Syndrome - genetics Marfan Syndrome - metabolism Marfan Syndrome - pathology Marfan's syndrome Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Microfilament Proteins - genetics Microfilament Proteins - metabolism Mutation Pathogenesis Personal computers Phenotype Proteins Reverse Transcriptase Polymerase Chain Reaction Stem cells Trends Variability |
| title | A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T19%3A49%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20new%20mouse%20model%20for%20marfan%20syndrome%20presents%20phenotypic%20variability%20associated%20with%20the%20genetic%20background%20and%20overall%20levels%20of%20Fbn1%20expression&rft.jtitle=PloS%20one&rft.au=Lima,%20Bruno%20L&rft.date=2010-11-30&rft.volume=5&rft.issue=11&rft.spage=e14136&rft.epage=e14136&rft.pages=e14136-e14136&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0014136&rft_dat=%3Cgale_plos_%3EA473829797%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1292463521&rft_id=info:pmid/21152435&rft_galeid=A473829797&rft_doaj_id=oai_doaj_org_article_29c9cf84a79c4a6a9562b9371c064c81&rfr_iscdi=true |