The mgΔlpn mouse model for Marfan syndrome recapitulates the ocular phenotypes of the disease

Souza, Rodrigo Barbosa de; Gyuricza, Isabela Gerdes; Cassiano, Luara Lucena; Farinha-Arcieri, Luis Ernesto; Liberatore, Ana Maria Alvim; Carmo, Sheila Schuindt do; Caldeira, Waldir; Cruz, Marcio V.; Ribeiro, Alberto F.; Tedesco, Roberto; Reinhardt, Dieter P.; Smith, Ricardo Luiz; Koh, Ivan Hong Jun; Pereira, Lygia V.

doi:10.1016/j.exer.2021.108461

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…The eye of the mouse is structurally different from the human. The spherical lens takes up much of the eyeball (see Figure 1A of Souza et al 2021 ) and the optic nerve and retina are different from human eyes ( Levkovitch-Verbin 2004 ). Both fibrillin-1 and fibrillin-2 were detected in the zonule of wild-type adult mice but the zonule of adult humans only contained fibrillin-1 ( Beene et al 2013 ; Hubmacher et al 2014 ).…”

Section: Fibrillin-1 and Marfan Syndromementioning

confidence: 99%

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Genetic models of fibrillinopathies

Summers

2023

Genetics

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The fibrillinopathies represent a group of diseases in which the 10–12 nm extracellular microfibrils are disrupted by genetic variants in one of the genes encoding fibrillin molecules, large glycoproteins of the extracellular matrix. The best-known fibrillinopathy is Marfan syndrome, an autosomal dominant condition affecting the cardiovascular, ocular, skeletal, and other systems, with a prevalence of around 1 in 3,000 across all ethnic groups. It is caused by variants of the FBN1 gene, encoding fibrillin-1, which interacts with elastin to provide strength and elasticity to connective tissues. A number of mouse models have been created in an attempt to replicate the human phenotype, although all have limitations. There are also natural bovine models and engineered models in pig and rabbit. Variants in FBN2 encoding fibrillin-2 cause congenital contractural arachnodactyly and mouse models for this condition have also been produced. In most animals, including birds, reptiles, and amphibians, there is a third fibrillin, fibrillin-3 (FBN3 gene) for which the creation of models has been difficult as the gene is degenerate and nonfunctional in mice and rats. Other eukaryotes such as the nematode C. elegans and zebrafish D. rerio have a gene with some homology to fibrillins and models have been used to discover more about the function of this family of proteins. This review looks at the phenotype, inheritance, and relevance of the various animal models for the different fibrillinopathies.

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Section: Fibrillin-1 and Marfan Syndromementioning

confidence: 99%

“…It is not known whether fibrillin-2 might contribute to the fibers in these cases. The ocular phenotype of the mgΔloxPneo ( Table 2 ) model has recently been examined ( Souza et al 2021 ). Heterozygous mice on the C57BL/6 background were found to have ectopia lentis with virtual absence of the zonular fibers.…”

Section: Fibrillin-1 and Marfan Syndromementioning

confidence: 99%

Genetic models of fibrillinopathies

Summers

2023

Genetics

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“…While several mouse models of MFS exist ( 13 – 16 ), we focus here on the mg

strain ( 16 ). mg

mice display classic phenotypic features of patients with MFS, including skeletal kyphosis and ocular defects, as well as enlargement of peripheral air spaces and compromised alveolar wall structures ( 16 – 18 ). Vascular manifestations of MFS in mg

mice encompass thickening of the aortic media, disruption of the elastic fiber network, and formation of thoracic aortic aneurysms.…”

Section: Introductionmentioning

confidence: 99%

The Fbn1 gene variant governs passive ascending aortic mechanics in the mgΔlpn mouse model of Marfan syndrome when superimposed to perlecan haploinsufficiency

Tarraf,

de Souza,

Herrick

et al. 2024

Front. Cardiovasc. Med.

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IntroductionAscending thoracic aortic aneurysms arise from pathological tissue remodeling that leads to abnormal wall dilation and increases the risk of fatal dissection/rupture. Large variability in disease manifestations across family members who carry a causative genetic variant for thoracic aortic aneurysms suggests that genetic modifiers may exacerbate clinical outcomes. Decreased perlecan expression in the aorta of mgΔlpn mice with severe Marfan syndrome phenotype advocates for exploring perlecan-encoding Hspg2 as a candidate modifier gene.MethodsTo determine the effect of concurrent Hspg2 and Fbn1 mutations on the progression of thoracic aortopathy, we characterized the microstructure and passive mechanical response of the ascending thoracic aorta in female mice of four genetic backgrounds: wild-type, heterozygous with a mutation in the Fbn1 gene (mgΔlpn), heterozygous with a mutation in the Hspg2 gene (Hspg2+/−), and double mutants carrying both the Fbn1 and Hspg2 variants (dMut).ResultsElastic fiber fragmentation and medial disarray progress from the internal elastic lamina outward as the ascending thoracic aorta dilates in mgΔlpn and dMut mice. Concurrent increase in total collagen content relative to elastin reduces energy storage capacity and cyclic distensibility of aortic tissues from mice that carry the Fbn1 variant. Inherent circumferential tissue stiffening strongly correlates with the severity of aortic dilatation in mgΔlpn and dMut mice. Perlecan haploinsufficiency superimposed to the mgΔlpn mutation curbs the viability of dMut mice, increases the occurrence of aortic enlargement, and reduces the axial stretch in aortic tissues.DiscussionOverall, our findings show that dMut mice are more vulnerable than mgΔlpn mice without an Hspg2 mutation, yet later endpoints and additional structural and functional readouts are needed to identify causative mechanisms.

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“…One such model is the mg∆ loxP neo mouse [61]. mg∆ loxP neo mice display some of the classic phenotypic features associated with patients with MFS, including enlargement of peripheral air spaces, compromised alveolar wall structures, as well as skeletal kyphosis and ocular defects [61,236,239]. Vascular manifestations include thickening of the aortic media, disruption of the elastic fiber network, and formation of thoracic aneurysms.…”

Section: Introductionmentioning

confidence: 99%

Development of a methodological framework to probe regional mechanics of the aneurysmal ascending thoracic aorta

Tarraf

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The mgΔlpn mouse model for Marfan syndrome recapitulates the ocular phenotypes of the disease

Cited by 6 publications

References 25 publications

Genetic models of fibrillinopathies

Genetic models of fibrillinopathies

The Fbn1 gene variant governs passive ascending aortic mechanics in the mgΔlpn mouse model of Marfan syndrome when superimposed to perlecan haploinsufficiency

Development of a methodological framework to probe regional mechanics of the aneurysmal ascending thoracic aorta

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