Marfan syndrome is a genetic disorder affecting the body’s connective tissue, which provides support, strength, and elasticity to various structures. It can impact multiple organ systems, often involving the heart, blood vessels, eyes, bones, and joints. The severity of symptoms varies greatly among individuals.
The Genetic Root
Marfan syndrome arises from mutations in the FBN1 gene on chromosome 15. This gene provides instructions for producing fibrillin-1, a protein that forms microfibrils within the body’s extracellular matrix.
Microfibrils are essential for forming elastic fibers, which enable tissues like the skin, ligaments, and blood vessels to stretch and then return to their original shape. Beyond providing structural support, these microfibrils also regulate the availability of certain growth factors, such as transforming growth factor-beta (TGF-β). They essentially store TGF-β in an inactive form, releasing it when needed to control cell growth, division, and tissue repair processes. Therefore, fibrillin-1 is not just a building block but also a modulator of cellular signaling pathways.
How Gene Mutations Lead to Impaired Connective Tissue
A mutation in the FBN1 gene produces a defective fibrillin-1 protein. This altered protein cannot properly form microfibrils, compromising the structural integrity and elasticity of connective tissues throughout the body.
When microfibrils are deficient or abnormal, tissues that rely on them for strength and flexibility become weakened. This impairment can lead to a range of issues, including the weakening and stretching of blood vessel walls, particularly the aorta, which is the main artery carrying blood from the heart. Additionally, the defective microfibrils lose their ability to properly regulate TGF-β. This dysregulation can lead to an excess of active TGF-β, contributing to further tissue damage and abnormal cellular responses, which manifests in the various features observed in Marfan syndrome.
Inheritance and New Mutations
Marfan syndrome follows an autosomal dominant inheritance pattern. This means that an individual only needs to inherit one copy of the mutated FBN1 gene from a parent to develop the condition. If a parent has Marfan syndrome, there is a 50% chance that each child they have will inherit the mutated gene and thus the disorder.
Approximately 75% of Marfan syndrome cases are inherited from an affected parent. However, about 25% of cases arise from a de novo, or new, spontaneous mutation in the FBN1 gene. In these instances, the individual is the first in their family to have the condition, as the genetic change occurred during the formation of the egg or sperm cell, or very early in embryonic development, without being passed down from either parent.