Marfan syndrome is a systemic genetic disorder that fundamentally disrupts the body’s connective tissue. Connective tissue acts as the body’s support structure, providing strength, flexibility, and elasticity to various organs and systems. Because this tissue is ubiquitous, the condition affects multiple parts of the body, leading to a wide array of symptoms. The most serious complications typically manifest in the cardiovascular, skeletal, and ocular systems.
The Core Genetic Factor
The single cause of Marfan syndrome is a mutation in the FBN1 gene, which resides on chromosome 15. This gene holds the instructions for producing the protein Fibrillin-1. A defect in the FBN1 gene results in the body creating an abnormal, dysfunctional version of Fibrillin-1. This abnormal protein triggers the disorder throughout the body’s connective tissue network and is the direct cause of the structural defects seen in the disorder.
Mechanism of Connective Tissue Dysfunction
Fibrillin-1 normally assembles into long, thread-like microfibrils. These microfibrils are the foundational components of elastic fibers, allowing connective tissues (like those in the skin, ligaments, and major blood vessels) to stretch and recoil. When the FBN1 gene is mutated, the resulting Fibrillin-1 protein cannot properly integrate into these microfibrils. This leads to weakened, fragmented, and less resilient connective tissue, accounting for features such as loose joints, elongated limbs, and defects in the heart and blood vessels.
Beyond its structural role, Fibrillin-1 also regulates a crucial signaling molecule called Transforming Growth Factor-beta (TGF-beta). In healthy individuals, Fibrillin-1 microfibrils bind to the latent, inactive form of TGF-beta, keeping it stored and controlled. The defective Fibrillin-1 protein is unable to perform this storage function effectively.
This failure leads to an excessive, unregulated release and activation of TGF-beta within the tissues. Elevated TGF-beta signaling promotes an inflammatory response and triggers the overproduction of enzymes that actively degrade the surrounding extracellular matrix. This process further weakens the connective tissue, contributing significantly to the pathology, particularly the progressive weakening and dangerous enlargement of the aorta.
How the Mutation is Acquired
Marfan syndrome is inherited in an autosomal dominant pattern, meaning a person only needs to inherit one copy of the mutated FBN1 gene to develop the condition. When one parent has the syndrome, there is a 50% chance that their child will inherit the affected gene and also have the disorder. Approximately 75% of Marfan syndrome cases result from this direct inheritance from an affected parent.
The remaining 25% of cases are the result of a de novo or spontaneous mutation. In these instances, the genetic change occurs for the first time in the affected individual, typically at the time of conception, and neither parent carries the mutation. This distinction means that a person can acquire the condition even if there is no previous family history. Regardless of whether the mutation is inherited or spontaneous, the underlying genetic cause—the defect in the FBN1 gene—remains the same.