10 Questions
What is the approximate incidence of Marfan syndrome?
1 in 5000
What is the percentage of patients with Marfan syndrome who have de novo mutations?
25% to 35%
What is the primary function of fibrillin 1?
To form microfibrils in both elastic and nonelastic tissues
What is the suggested pathogenesis of Marfan syndrome based on studies of fibrillin 1 deposition and cell culture expression assays?
Dominant negative
What is the name of the syndrome that is caused by mutations in FBN1 and characterized by marfanoid signs, including mitral valve prolapse or myopia, borderline and nonprogressive aortic enlargement, and nonspecific skeletal and skin findings?
MASS phenotype
What is the primary role of fibrillin 1 microfibrils in the TGFβ superfamily?
To bind and reduce the concentration of growth factors
What is the consequence of losing fibrillin 1 in terms of TGFβ signaling?
An increase in the local abundance of unbound TGFβ
What is the significance of the rescue by TGFβ antagonists in fibrillin 1-deficient mice?
It shows that TGFβ antagonists can reverse the pulmonary and vascular changes
What is the current understanding of Marfan syndrome based on recent evidence in mouse models?
It is a result of the abnormal activation of TGFβ signaling
What is the relationship between intrafamilial and interfamilial variability and the phenotype of Marfan syndrome?
The variability suggests that environmental and epigenetic factors play a significant role in determining the phenotype
Study Notes
Marfan Syndrome
- Marfan syndrome is a panethnic, autosomal dominant, connective tissue disorder caused by mutations in the fibrillin 1 gene (FBN1).
- The incidence of Marfan syndrome is approximately 1 in 5000.
- 25-35% of patients have de novo mutations.
Genetics
- Mutations leading to Marfan syndrome are scattered across the FBN1 gene, with each mutation usually unique to a family.
- FBN1 encodes fibrillin 1, an extracellular matrix glycoprotein with a wide distribution in elastic and nonelastic tissues.
Pathogenesis
- Mutations affect fibrillin 1 synthesis, processing, secretion, polymerization, or stability.
- Production of mutant fibrillin 1 inhibits formation of normal microfibrils or stimulates inappropriate proteolysis of extracellular microfibrils.
- Half-normal amounts of normal fibrillin 1 may be insufficient for effective microfibrillar assembly, contributing to disease pathogenesis through haploinsufficiency.
Related Syndromes
- Mutations in FBN1 can also cause neonatal Marfan syndrome, isolated skeletal features, autosomal dominant ectopia lentis, and the MASS phenotype.
Phenotype and Genotype
- Phenotypes are fairly consistent within a family, but the severity may vary considerably.
- Clear genotype-phenotype correlations have not emerged, suggesting environmental and epigenetic factors play a significant role in determining the phenotype.
Fibrillin 1 Function
- Fibrillin 1 microfibrils normally bind and reduce the concentration and activity of growth factors in the TGFβ superfamily.
- Loss of fibrillin 1 leads to an increase in local abundance and activity of unbound TGFβ, contributing significantly to the pathogenesis.
Learn about the causes and incidence of Marfan syndrome, a connective tissue disorder resulting from mutations in the FBN1 gene. Discover the pathogenesis and characteristics of this autosomal dominant condition.
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