{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:19:11Z","timestamp":1790849951157,"version":"4.1.0"},"reference-count":56,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":1233,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"funder":[{"name":"National Key Research and Development Program National Key Research and Development Program of China","award":["2017YFA0105101"],"award-info":[{"award-number":["2017YFA0105101"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Variable clinical differences have been observed between the FBN1 gene mutation and the classical Marfan phenotype in humans. Although FBN1 knockout (KO), or dominant negative mutant mice are widely used as an animal model for MFS, these mice cannot recapitulate the genotype\/phenotype relationship of Marfanoid-progeroid-lipodystrophy syndrome (MPL), a syndrome caused by a mutation in the C-terminus of fibrillin-1, the penultimate exon of the FBN1 gene. Here we describe the generation of a rabbit MPL model with C-terminal truncation of fibrillin-1 using a CRISPR\/Cas9 system. FBN1 Heterozygous (FBN1 Het) rabbits faithfully recapitulated the phenotypes of MFS, including muscle wasting and impaired connective tissue, ocular syndrome and aortic dilation. Moreover, skin symptoms, lipodystrophy, growth retardation and dysglycemia were also seen in these FBN1 Het rabbits, which have not been reported in other animal models. In conclusion, this novel rabbit model mimics the histopathological changes and functional defects of MPL syndrome, and may become a valuable model for studies of pathogenesis and drug screening for MPL syndrome.<\/jats:p>","DOI":"10.1242\/dmm.031542","type":"journal-article","created":{"date-parts":[[2018,3,14]],"date-time":"2018-03-14T17:45:24Z","timestamp":1521049524000},"source":"Crossref","is-referenced-by-count":19,"title":["Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit"],"prefix":"10.1242","author":[{"given":"Mao","family":"Chen","sequence":"first","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Yao","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiangbing","family":"Yang","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jichao","family":"Deng","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Song","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Sui","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Zhou","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haobing","family":"Yao","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongsheng","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daxin","family":"Pang","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9567-2330","authenticated-orcid":false,"given":"Zhanjun","family":"Li","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangxue","family":"Lai","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China"},{"name":"Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2018,1,1]]},"reference":[{"key":"2021042500182414300_DMM031542C1","first-page":"2369","article-title":"Decreased Aortic Elasticity in Children With Marfan Syndrome or Loeys-Dietz Syndrome","volume":"80","author":"Akazawa","year":"2016","journal-title":"Circ. J."},{"key":"2021042500182414300_DMM031542C2","first-page":"2764","article-title":"The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele","volume":"24","author":"Aubart","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2021042500182414300_DMM031542C3","first-page":"11922","article-title":"Nanostructure of fibrillin-1 reveals compact conformation of EGF arrays and mechanism for extensibility","volume":"103","author":"Baldock","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042500182414300_DMM031542C4","first-page":"633","article-title":"Muscle fibrillin deficiency in Marfan's syndrome myopathy","volume":"74","author":"Behan","year":"2003","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"2021042500182414300_DMM031542C5","first-page":"159","article-title":"An animal model of the Marfan syndrome","volume":"37","author":"Besser","year":"1990","journal-title":"Am. J. Med. Genet."},{"key":"2021042500182414300_DMM031542C116","first-page":"1754","article-title":"A nonsense mutation in the fibrillin-1 gene of a Marfan syndrome patient induces NMD and disrupts an exonic splicing enhancer","volume":"16","author":"Caputi","year":"2002","journal-title":"Genes Dev."},{"key":"2021042500182414300_DMM031542C6","first-page":"8016","article-title":"Fibrillins 1 and 2 perform partially overlapping functions during aortic development","volume":"281","author":"Carta","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021042500182414300_DMM031542C7","first-page":"284","article-title":"The revised ghent nosology; reclassifying isolated ectopia lentis","volume":"87","author":"Chandra","year":"2015","journal-title":"Clin. Genet."},{"key":"2021042500182414300_DMM031542C8","first-page":"635","article-title":"Structure and function of the mammalian fibrillin gene family: implications for human connective tissue diseases","volume":"107","author":"Davis","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"2021042500182414300_DMM031542C9","first-page":"174","article-title":"Expression of FBN1 during adipogenesis: relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions","volume":"119","author":"Davis","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"2021042500182414300_DMM031542C10","first-page":"1444","article-title":"Asprosin is a centrally acting orexigenic hormone","volume":"23","author":"Duerrschmid","year":"2017","journal-title":"Nat. Med."},{"key":"2021042500182414300_DMM031542C11","first-page":"1341","article-title":"De novo heterozygous FBN1 mutations in the extreme C-terminal region cause progeroid fibrillinopathy","volume":"164A","author":"Garg","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042500182414300_DMM031542C12","first-page":"1104","article-title":"Animal Models of Atherosclerosis","volume":"32","author":"Getz","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021042500182414300_DMM031542C13","first-page":"717","article-title":"Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3\u2019 end of the FBN1 gene","volume":"155a","author":"Goldblatt","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042500182414300_DMM031542C14","first-page":"97","article-title":"An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death","volume":"49","author":"Granata","year":"2016","journal-title":"Nat. Genet."},{"key":"2021042500182414300_DMM031542C15","first-page":"2749","article-title":"Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3\u2019 terminus of the FBN1-gene","volume":"152A","author":"Graul-Neumann","year":"2010","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042500182414300_DMM031542C16","first-page":"247","article-title":"A rapid and general assay for monitoring endogenous gene modification","volume":"649","author":"Guschin","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"2021042500182414300_DMM031542C17","first-page":"117","article-title":"Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome","volume":"312","author":"Habashi","year":"2006","journal-title":"Science"},{"key":"2021042500182414300_DMM031542C18","first-page":"1369","article-title":"Muscle and bone impairment in children with Marfan syndrome: correlation with age and FBN1 genotype","volume":"30","author":"Haine","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"2021042500182414300_DMM031542C19","first-page":"726","article-title":"Developmental anatomy in the zonular connection with lens capsule in macaque eye","volume":"296","author":"Hiraoka","year":"2013","journal-title":"Anat Rec (Hoboken)"},{"key":"2021042500182414300_DMM031542C20","first-page":"6548","article-title":"Biogenesis of extracellular microfibrils: Multimerization of the fibrillin-1 C terminus into bead-like structures enables self-assembly","volume":"105","author":"Hubmacher","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042500182414300_DMM031542C21","first-page":"2269","article-title":"Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: a potential modifier of phenotype?","volume":"12","author":"Hutchinson","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"2021042500182414300_DMM031542C22","first-page":"482","article-title":"Development of the oxytalan fiber system in the rat molar periodontal ligament evaluated by light- and electron-microscopic analyses","volume":"194","author":"Inoue","year":"2012","journal-title":"Ann. Anat."},{"key":"2021042500182414300_DMM031542C23","first-page":"230","article-title":"Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3\u2019 end of FBN1 gene","volume":"57","author":"Jacquinet","year":"2014","journal-title":"Eur. J. Med. Genet."},{"key":"2021042500182414300_DMM031542C24","first-page":"827","article-title":"New insights into the structure, assembly and biological roles of 10-12 nm connective tissue microfibrils from fibrillin-1 studies","volume":"473","author":"Jensen","year":"2016","journal-title":"Biochem. J."},{"key":"2021042500182414300_DMM031542C26","first-page":"10155","article-title":"C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43","volume":"111","author":"Jensen","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042500182414300_DMM031542C27","first-page":"172","article-title":"Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome","volume":"114","author":"Judge","year":"2004","journal-title":"J. Clin. Invest."},{"key":"2021042500182414300_DMM031542C28","first-page":"26","article-title":"Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure","volume":"32","author":"Karimi","year":"2016","journal-title":"Can. J. Cardiol."},{"key":"2021042500182414300_DMM031542C29","first-page":"e14136","article-title":"A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression","volume":"5","author":"Lima","year":"2010","journal-title":"PLoS One"},{"key":"2021042500182414300_DMM031542C30","first-page":"235","article-title":"The morphology and thickness of cornea in patients with Marfan syndrome","volume":"47","author":"Liu","year":"2011","journal-title":"Zhonghua Yan Ke Za Zhi"},{"key":"2021042500182414300_DMM031542C31","first-page":"476","article-title":"The revised Ghent nosology for the Marfan syndrome","volume":"47","author":"Loeys","year":"2010","journal-title":"J. Med. Genet."},{"key":"2021042500182414300_DMM031542C32","first-page":"2039","article-title":"Evidence for furin-type activity-mediated C-terminal processing of profibrillin-1 and interference in the processing by certain mutations","volume":"7","author":"L\u00f6nnqvist","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"2021042500182414300_DMM031542C33","first-page":"1355","article-title":"Quantitative sequence analysis of FBN1 premature termination codons provides evidence for incomplete NMD in leukocytes","volume":"30","author":"Magyar","year":"2009","journal-title":"Hum. Mutat."},{"key":"2021042500182414300_DMM031542C35","first-page":"407","article-title":"Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome","volume":"33","author":"Neptune","year":"2003","journal-title":"Nat. Genet."},{"key":"2021042500182414300_DMM031542C36","first-page":"1244","article-title":"Marfanoid-progeroid-lipodystrophy syndrome: a newly recognized fibrillinopathy","volume":"24","author":"Passarge","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"2021042500182414300_DMM031542C37","first-page":"55","article-title":"Marfan syndrome: current perspectives","volume":"9","author":"Pepe","year":"2016","journal-title":"Appl Clin Genet"},{"key":"2021042500182414300_DMM031542C38","first-page":"218","article-title":"Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome","volume":"17","author":"Pereira","year":"1997","journal-title":"Nat. Genet."},{"key":"2021042500182414300_DMM031542C39","first-page":"3819","article-title":"Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-l","volume":"96","author":"Pereira","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021042500182414300_DMM031542C40","first-page":"83","article-title":"Isolation and culture of skin fibroblasts","volume":"117","author":"Rittie","year":"2005","journal-title":"Methods Mol. Med."},{"key":"2021042500182414300_DMM031542C41","first-page":"566","article-title":"Asprosin, a Fasting-Induced Glucogenic Protein Hormone","volume":"165","author":"Romere","year":"2016","journal-title":"Cell"},{"key":"2021042500182414300_DMM031542C42","first-page":"279","article-title":"FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders","volume":"591","author":"Sakai","year":"2016","journal-title":"Gene"},{"key":"2021042500182414300_DMM031542C43","first-page":"223","article-title":"Premature termination mutations in FBN1: distinct effects on differential allelic expression and on protein and clinical phenotypes","volume":"71","author":"Schrijver","year":"2002","journal-title":"Am. J. Hum. 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Genet."},{"key":"2021042500182414300_DMM031542C47","doi-asserted-by":"crossref","DOI":"10.1093\/hmg\/ddw125","article-title":"CRISPR\/Cas9-mediated mutation of PHEX in rabbit recapitulates human X-linked hypophosphatemia (XLH)","author":"Sui","year":"2016","journal-title":"Hum. Mol. Genet"},{"key":"2021042500182414300_DMM031542C48","first-page":"3057","article-title":"Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype","volume":"161A","author":"Takenouchi","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042500182414300_DMM031542C49","first-page":"545","article-title":"The diagnostic value of the facial features of Marfan syndrome","volume":"4","author":"Ting","year":"2010","journal-title":"J. Child Orthop."},{"key":"2021042500182414300_DMM031542C50","first-page":"24413","article-title":"Generation of heterozygous fibrillin-1 mutant cloned pigs from genome-edited foetal fibroblasts","volume":"6","author":"Umeyama","year":"2016","journal-title":"Sci. Rep."},{"key":"2021042500182414300_DMM031542C51","first-page":"815","article-title":"CRISPR-Cas9-mediated genome editing in one blastomere of two-cell embryos reveals a novel Tet3 function in regulating neocortical development","volume":"27","author":"Wang","year":"2017","journal-title":"Cell Res."},{"key":"2021042500182414300_DMM031542C52","first-page":"657","article-title":"Dermal tissue and cellular expression of fibrillin-1 in diffuse cutaneous systemic sclerosis","volume":"49","author":"Wipff","year":"2010","journal-title":"Rheumatology (Oxf.)"},{"key":"2021042500182414300_DMM031542C53","first-page":"12","article-title":"Generation of multi-gene knockout rabbits using the Cas9\/gRNA system","volume":"3","author":"Yan","year":"2014","journal-title":"Cell Regen (Lond)"},{"key":"2021042500182414300_DMM031542C54","first-page":"e104091","article-title":"A maladaptive role for EP4 receptors in mouse mesangial cells","volume":"9","author":"Yang","year":"2014","journal-title":"PLoS One"},{"key":"2021042500182414300_DMM031542C55","first-page":"22024","article-title":"CRISPR\/Cas9-mediated GJA8 knockout in rabbits recapitulates human congenital cataracts","volume":"6","author":"Yuan","year":"2016","journal-title":"Sci. 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