What is Marfan Syndrome?

Marfan Syndrome (MFS) is an autosomal dominant inherited disorder of connective tissue affecting multiple systems, including the skeletal, ocular, and cardiovascular systems. Patients typically present with disproportionately long limbs (dolichostenomelia), scoliosis, ectopia lentis, severe myopia, and most critically, aortic root dilation and dissecting aneurysms. Aortic complications are the leading cause of mortality in Marfan Syndrome patients. The incidence is approximately 1 in 5,000 individuals, with about 75% of cases having a family history and 25% arising from spontaneous mutations.
 

Pathogenesis
 

The core pathogenesis of Marfan Syndrome is primarily caused by mutations in the FBN1 gene located at chromosome 15q21.1. This gene encodes fibrillin-1, a major structural component of the extracellular matrix microfibrils. Mutations in fibrillin-1 lead to abnormal elastic fiber structure and disrupt collagen metabolism. When connective tissue fibers are defective, organ systems throughout the body are affected, particularly the skeletal and cardiovascular systems.

Common FBN1 mutation types include:

● Missense Mutations (53%-56.1%): Examples include c.6820T>G p.(Cys2274Gly) and c.3605G>T. These mutations often cause protein misfolding and increase susceptibility to proteolysis, correlating with severe ocular manifestations like ectopia lentis.

● Nonsense, Frameshift, and Large Deletion Mutations (~25%): Examples include c.4120delC, c.7038_7039del, and c.7412delC. These variants typically introduce premature termination codons, producing truncated proteins, and are strongly associated with higher cardiovascular risk, such as aortic dissection.

● Splice Site Mutations (~12%): Example: the intronic variant c.3464-5_3464-4delGAinsAG, which disrupts normal mRNA splicing.

● Base Variants in Intronic Splice Regions: These can lead to aberrant splicing events like exon skipping.

Research indicates that exons 24-32 constitute a mutation hotspot. Missense mutations in this region (e.g., the classic C1039G) are often associated with severe neonatal or early-onset Marfan Syndrome.
 

Furthermore, studies show that Marfan Syndrome pathogenesis is also linked to dysregulation of the Transforming Growth Factor-beta (TGF-β) signaling pathway. FBN1 mutations in MFS patients cause the release of excessive amounts of active TGFβ from the extracellular matrix. The consequent overactivation of TGF-β signaling promotes vascular smooth muscle cell apoptosis and extracellular matrix degradation, ultimately leading to structural weakening of the aortic wall.

(Image: PubMed. Mechanism of TGF-β Pathway Dysregulation Caused by FBN1 Gene Mutations)

 

(Image: PubMed. Core Molecular Mechanism of Aortic Aneurysm Formation Due to FBN1 Mutation)

Gene Therapy
 

1. Gene Replacement Therapy: Utilizes adeno-associated virus (AAV) vectors to deliver a functional FBN1 gene into patients, aiming to restore normal fibrillin-1 expression.

2. Gene Silencing Technology: Employs small interfering RNA (siRNA) or antisense oligonucleotide (ASO) technology to specifically silence the mutant FBN1 allele, reducing the production of abnormal protein.

3. Signal Pathway Modulation: Aims to mitigate aortic disease progression by inhibiting the dysregulated TGF-β signaling pathway.
 

Mouse Models
 

● FBN1C1039G/+ Mice: Carry a missense mutation in mouse FBN1 exon 25. Mice homozygous for this mutation (FBN1C1039G/C1039G) often die perinatally due to vascular abnormalities. Heterozygous FBN1C1039G/+ mice have a normal lifespan and recapitulate core features of human MFS.

● mgΔloxPneo Mouse Model: FBN1 exons 19-24 are replaced by loxP and neo sequences. These mice exhibit clear MFS-like phenotypes. They can also be crossed with Cre driver mice to study FBN1 function in specific tissues or developmental stages.

● Fbn1mgR/mgR Mice: A Neo cassette is inserted between exons 18 and 19. Homozygous mice display severe skeletal abnormalities and prominent vascular system defects, frequently dying in early adulthood from aortic complications like aneurysm or dissection.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various MFS mouse models according to client needs, such as FBN1C1039G/+ mice, mgΔloxPneo mice, and Fbn1mgR/mgR mice. We welcome inquiries!

 

References:

[1] Jiang Y, Jia P, Feng X, Zhang D. Marfan syndrome: insights from animal models. Front Genet. 2025 Jan 6;15:1463318. doi: 10.3389/fgene.2024.1463318. PMID: 39834548; PMCID: PMC11743488.

[2] Lima BL, Santos EJ, Fernandes GR, Merkel C, Mello MR, Gomes JP, Soukoyan M, Kerkis A, Massironi SM, Visintin JA, Pereira LV. A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression. PLoS One. 2010 Nov 30;5(11):e14136. doi: 10.1371/journal.pone.0014136. PMID: 21152435; PMCID: PMC2994728.

[3] Asta L, D'Angelo GA, Marinelli D, Benedetto U. Genetic Basis, New Diagnostic Approaches, and Updated Therapeutic Strategies of the Syndromic Aortic Diseases: Marfan, Loeys-Dietz, and Vascular Ehlers-Danlos Syndrome. Int J Environ Res Public Health. 2023 Aug 20;20(16):6615. doi: 10.3390/ijerph20166615. PMID: 37623198; PMCID: PMC10454608.

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