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Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit
- Source :
- Disease Models & Mechanisms, Vol 11, Iss 4 (2018), Disease Models & Mechanisms
- Publication Year :
- 2018
- Publisher :
- The Company of Biologists, 2018.
-
Abstract
- 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.<br />Summary: A novel genetically engineered rabbit model of MPL syndrome, generated by CRISPR/Cas9-mediated mutation of FBN1, mimics the histopathological changes and functional defects of MPL syndrome seen in the clinic.
- Subjects :
- 0301 basic medicine
Marfan syndrome
Pathology
Lipodystrophy
Fibrillin-1
Medicine (miscellaneous)
lcsh:Medicine
Rabbit
Gene mutation
Eye
Marfan Syndrome
Pathogenesis
Exon
0302 clinical medicine
Immunology and Microbiology (miscellaneous)
skin and connective tissue diseases
Aorta
Skin
Marfanoid-progeroid-lipodystrophy (MPL) syndrome
Marfanoid
Ear
Phenotype
Growth and Development
Rabbits
Fibrillin
Dilatation, Pathologic
lcsh:RB1-214
musculoskeletal diseases
Heterozygote
medicine.medical_specialty
congenital, hereditary, and neonatal diseases and abnormalities
Neuroscience (miscellaneous)
Biology
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
medicine
lcsh:Pathology
Animals
Amino Acid Sequence
Resource Article
Muscle, Skeletal
CRISPR/Cas9
Base Sequence
Wasting Syndrome
lcsh:R
Elastic Tissue
medicine.disease
Cartilage
Glucose
030104 developmental biology
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 17548411 and 17548403
- Volume :
- 11
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Disease Models & Mechanisms
- Accession number :
- edsair.doi.dedup.....8a3f635f10c2fe6a9af381f344163851