Marfan Syndrome is a systemic genetic disorder that affects the body’s connective tissue. Connective tissue provides the framework, strength, and elasticity for many organs and structures, including the heart, blood vessels, eyes, and skeleton. The disorder is present from birth, and its effects can range widely in severity among individuals. This condition is fundamentally caused by a defect in a single gene, which compromises the integrity of connective tissue across multiple body systems.
The Role of the FBN1 Gene
The primary cause of Marfan Syndrome is a mutation in the FBN1 gene, located on chromosome 15. This gene provides the instructions the body needs to create the large protein called Fibrillin-1. More than 1,300 different mutations in the FBN1 gene have been identified that can lead to the syndrome. These mutations cause the disorder by reducing the amount of Fibrillin-1 produced or by altering the protein’s structure so that it cannot function properly.
Fibrillin-1 Dysfunction and Microfibril Damage
Fibrillin-1 is a component of the extracellular matrix, the lattice of proteins and molecules that fills the spaces between cells. This protein links together to form thread-like structures called microfibrils. Microfibrils act like scaffolding for connective tissue, providing tensile strength and elasticity in areas like the aorta, ligaments, and the lens of the eye. When the FBN1 gene is mutated, the defective Fibrillin-1 impairs microfibril formation. This structural failure leads directly to weakened connective tissue that cannot withstand normal mechanical stresses.
TGF-β Dysregulation
Faulty microfibrils also affect growth factor signaling. Normally, microfibrils bind to and sequester a powerful signaling molecule known as Transforming Growth Factor Beta (TGF-β), keeping it inactive. Defective microfibrils fail to properly store latent TGF-β, leading to its excessive activation in the tissues. This overactive TGF-β causes further damage to the connective tissue by promoting inflammation and degradation.
How Marfan Syndrome is Acquired
Marfan Syndrome is inherited in an autosomal dominant pattern. This means a person only needs to inherit one copy of the mutated FBN1 gene from either parent to develop the condition. An affected parent has a 50% chance of passing the mutation to any child.
The majority of cases (approximately 75%) are inherited directly from a parent who has the condition. The remaining 25% of cases occur in individuals with no prior family history. These instances result from a de novo, or spontaneous, genetic mutation that happens randomly in the sperm or egg cell before conception, or very early in fetal development. This new mutation means the individual is the first person in their family to have Marfan Syndrome.