Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit

Various clinical differences have been observed between patients with the FBN1 gene mutation and those with the classical Marfan phenotype. Although FBN1 knockout (KO) or dominant-negative mutant mice are widely used as an animal model for Marfan syndrome (MFS), these mice cannot recapitulate the ge...

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Main Authors: Mao Chen, Bing Yao, Qiangbing Yang, Jichao Deng, Yuning Song, Tingting Sui, Lina Zhou, HaoBing Yao, Yuanyuan Xu, Hongsheng Ouyang, Daxin Pang, Zhanjun Li, Liangxue Lai
Format: Article
Language:English
Published: The Company of Biologists 2018-04-01
Series:Disease Models & Mechanisms
Subjects:
Online Access:http://dmm.biologists.org/content/11/4/dmm031542
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author Mao Chen
Bing Yao
Qiangbing Yang
Jichao Deng
Yuning Song
Tingting Sui
Lina Zhou
HaoBing Yao
Yuanyuan Xu
Hongsheng Ouyang
Daxin Pang
Zhanjun Li
Liangxue Lai
author_facet Mao Chen
Bing Yao
Qiangbing Yang
Jichao Deng
Yuning Song
Tingting Sui
Lina Zhou
HaoBing Yao
Yuanyuan Xu
Hongsheng Ouyang
Daxin Pang
Zhanjun Li
Liangxue Lai
author_sort Mao Chen
collection DOAJ
description Various clinical differences have been observed between patients with the FBN1 gene mutation and those with the classical Marfan phenotype. Although FBN1 knockout (KO) or dominant-negative mutant mice are widely used as an animal model for Marfan syndrome (MFS), these mice cannot recapitulate the genotype/phenotype relationship of Marfanoid-progeroid-lipodystrophy (MPL) syndrome, which is 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, and 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 could become a valuable model for studies of pathogenesis and drug screening for MPL syndrome.
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spelling doaj.art-f503d2b367cb4b91a91f8416ce42aedd2022-12-22T00:21:16ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-04-0111410.1242/dmm.031542031542Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbitMao Chen0Bing Yao1Qiangbing Yang2Jichao Deng3Yuning Song4Tingting Sui5Lina Zhou6HaoBing Yao7Yuanyuan Xu8Hongsheng Ouyang9Daxin Pang10Zhanjun Li11Liangxue Lai12 Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China Various clinical differences have been observed between patients with the FBN1 gene mutation and those with the classical Marfan phenotype. Although FBN1 knockout (KO) or dominant-negative mutant mice are widely used as an animal model for Marfan syndrome (MFS), these mice cannot recapitulate the genotype/phenotype relationship of Marfanoid-progeroid-lipodystrophy (MPL) syndrome, which is 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, and 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 could become a valuable model for studies of pathogenesis and drug screening for MPL syndrome.http://dmm.biologists.org/content/11/4/dmm031542Fibrillin-1CRISPR/Cas9Marfanoid-progeroid-lipodystrophy (MPL) syndromeRabbit
spellingShingle Mao Chen
Bing Yao
Qiangbing Yang
Jichao Deng
Yuning Song
Tingting Sui
Lina Zhou
HaoBing Yao
Yuanyuan Xu
Hongsheng Ouyang
Daxin Pang
Zhanjun Li
Liangxue Lai
Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit
Disease Models & Mechanisms
Fibrillin-1
CRISPR/Cas9
Marfanoid-progeroid-lipodystrophy (MPL) syndrome
Rabbit
title Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit
title_full Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit
title_fullStr Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit
title_full_unstemmed Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit
title_short Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit
title_sort truncated c terminus of fibrillin 1 induces marfanoid progeroid lipodystrophy mpl syndrome in rabbit
topic Fibrillin-1
CRISPR/Cas9
Marfanoid-progeroid-lipodystrophy (MPL) syndrome
Rabbit
url http://dmm.biologists.org/content/11/4/dmm031542
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