Marfan syndrome (MFS) affects the body’s connective tissue. This condition is present from birth and affects multiple systems, including the skeleton, eyes, heart, and blood vessels. The underlying cause is a mutation in a single gene that leads to weakened and disorganized connective tissue throughout the body.
The FBN1 Gene: The Direct Genetic Cause
Marfan syndrome is caused by a mutation in the FBN1 gene, which is located on chromosome 15. This gene holds the instructions for making a protein called fibrillin-1. More than a thousand different mutations have been identified within the FBN1 gene that can lead to the syndrome.
These genetic errors often involve small changes, such as a point mutation, which alters a single building block of the DNA sequence. The resulting mutation causes the cell to either produce an insufficient amount of normal fibrillin-1 protein or a structurally abnormal version that cannot function properly. This disruption directly impairs the construction of healthy connective tissue throughout the body.
The Role of Fibrillin-1 in Connective Tissue
The fibrillin-1 protein is a major structural component of microfibrils, which are thread-like structures found in the extracellular matrix of connective tissue. These microfibrils act as a scaffold, providing strength, stability, and elasticity to tissues in the body. In healthy individuals, fibrillin-1 molecules assemble into these microfibrils, which are abundant in the aorta, ligaments, and the suspensory ligaments of the eye lens.
When the FBN1 gene is mutated, the resulting defective fibrillin-1 cannot properly form microfibril scaffolds. This structural failure causes the connective tissue to become weak, lax, and less elastic, leading to the physical characteristics observed in Marfan syndrome. This mechanical failure explains why the aorta, the body’s main artery, is prone to enlargement and tearing.
Fibrillin-1 also regulates the activity of a signaling molecule called Transforming Growth Factor-Beta (TGF-β). Normally, fibrillin-1 sequesters and controls TGF-β availability, preventing it from becoming overactive. In Marfan syndrome, defective fibrillin-1 releases an excessive amount of TGF-β, which contributes to tissue inflammation and degradation. This dysregulation drives the progression of the disease, particularly damage to the heart and blood vessels.
Understanding Autosomal Dominant Inheritance
Marfan syndrome is acquired through autosomal dominant inheritance. This means a person only needs to inherit one copy of the mutated FBN1 gene from one affected parent to develop the condition. This inheritance pattern accounts for approximately 75% of all Marfan syndrome cases.
The term “autosomal” indicates the FBN1 gene is located on a non-sex chromosome, meaning the condition affects males and females equally. A parent with Marfan syndrome has a 50% probability of passing the mutated gene copy to any child. The child has a 50% chance of inheriting the healthy copy and not developing the syndrome.
Spontaneous Genetic Changes (De Novo Mutations)
While most Marfan syndrome cases are inherited, the condition can also occur in individuals with no family history of the disorder. This is explained by a de novo mutation, meaning “new.” A de novo mutation occurs spontaneously in the FBN1 gene in the egg or sperm cell that formed the child, or very early in embryonic development.
In these instances, both parents have two normal copies of the FBN1 gene and are unaffected by the syndrome. This new mutation is not present in the parents’ genetic makeup, but it is present in the child’s. Approximately 25% of all Marfan syndrome diagnoses result from these spontaneous genetic changes. Once a de novo mutation has occurred, the affected individual has the same 50% chance of passing the condition to their own children.