Marfan syndrome is caused primarily by a **genetic mutation** in the gene called **FBN1**, which encodes the protein **fibrillin-1**. Fibrillin-1 is a crucial component of connective tissue, the material that supports and holds together many parts of the body such as the skin, bones, blood vessels, and eyes. When the FBN1 gene is mutated, the body produces defective fibrillin-1, which weakens the connective tissue and leads to the various symptoms seen in Marfan syndrome.
This mutation disrupts the structure and function of connective tissue throughout the body. Because connective tissue is found everywhere, the effects of the mutation are widespread, affecting the skeleton, cardiovascular system, eyes, and other organs. For example, the weakened connective tissue in the aorta (the large artery carrying blood from the heart) can cause it to enlarge or even rupture, which is a major health risk for people with Marfan syndrome. Similarly, the lens of the eye may become dislocated due to weak connective tissue holding it in place.
Marfan syndrome is inherited in an **autosomal dominant** pattern, meaning that only one copy of the mutated gene from either parent is enough to cause the disorder. About 75% of cases are inherited from an affected parent, while roughly 25% result from new mutations that occur spontaneously without a family history. The severity of symptoms can vary widely even within the same family, depending on how the mutation affects fibrillin-1 production and function.
On a molecular level, recent research has shown that these mutations not only affect the structure of fibrillin-1 but also alter how sugars are attached to the protein—a process called **O-glucosylation**. This modification is important for the protein’s stability and function. Changes in glucosylation patterns caused by the mutation may contribute to the tissue abnormalities seen in Marfan syndrome, although the exact mechanisms are still being studied.
The defective fibrillin-1 affects the **extracellular matrix (ECM)**, which is the network of proteins and molecules outside cells that provides structural support. When the ECM is compromised, tissues become weaker and more elastic than normal, leading to the characteristic features of Marfan syndrome such as:
– Tall, slender body with long arms, legs, fingers, and toes (arachnodactyly)
– Flexible or double-jointed limbs
– Chest deformities like pectus excavatum (sunken chest) or pectus carinatum (pigeon chest)
– Eye problems including lens dislocation, nearsightedness, glaucoma, and risk of retinal detachment
– Cardiovascular issues such as enlargement of the aorta (aortic aneurysm), aortic dissection (tear), mitral valve prolapse, and irregular heart rhythms
Other symptoms can include stretch marks unrelated to weight changes, spontaneous lung collapse (pneumothorax), and fatigue due to cardiovascular strain.
Besides FBN1, mutations in other genes like **AKT1** and **LMNA** are linked to disorders with overlapping features, but FBN1 mutations are the primary cause of Marfan syndrome specifically.
Because the underlying problem is a genetic defect affecting connective tissue, there is currently no cure that can fix the mutation itself. However, many symptoms can be managed or treated through surgery, medications, and careful monitoring, especially to prevent life-threatening complications like aortic rupture.
In summary, Marfan syndrome arises from a mutation in the FBN1 gene that leads to faulty fibrillin-1 protein, weakening connective tissue throughout the body and causing a wide range of skeletal, cardiovascular, and ocular problems. The genetic nature and molecular effects of this mutation explain the diverse and systemic manifestations of the syndrome.
