Abstract
ABSTRACTVarious 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.
Highlights
Different mutations in the FBN1 gene lead to a wide range of diseases, such as Marfan syndrome (MFS), Weill–Marchesani syndrome, acromelic dysplasias, stiff skin syndrome and Marfanoid-progeroid-lipodystrophy (MPL) syndrome (Pepe et al, 2016)
Generation and MPL phenotype of FBN1 Het rabbits The C-terminus of fibrillin-1, which contains a glucogenic hormone, correlates with lipodystrophy in MPL patients
These results demonstrated that mutations in FBN1 can be achieved via the CRISPR/Cas9 system with high efficiency in rabbits
Summary
Different mutations in the FBN1 gene lead to a wide range of diseases, such as Marfan syndrome (MFS), Weill–Marchesani syndrome, acromelic dysplasias, stiff skin syndrome and Marfanoid-progeroid-lipodystrophy (MPL) syndrome (Pepe et al, 2016). The FBN1 gene consists of 66 exons and has seven main protein domains, including a calcium-binding domain (cbEGF), noncalcium-binding domain, TGF-β-binding protein-like domain, L.Z., 0000-0002-9567-2330; L.L., 0000-0003-4628-7513. The C-terminus was required for secretion and self-assembly of fibrillin at the cellular level (Hubmacher et al, 2008; Jensen et al, 2014), the pathogenesis of MPL syndrome is not clear in the animal model
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