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URL of this page: https://medlineplus.gov/genetics/gene/fbn1/

FBN1 gene

fibrillin 1

Normal Function

The FBN1 gene provides instructions for making a large protein called fibrillin-1. This protein is transported out of cells into the extracellular matrix, which is an intricate lattice of proteins and other molecules that forms in the spaces between cells. In the extracellular matrix, fibrillin-1 proteins bind to each other and to other proteins to form threadlike filaments called microfibrils, which are organized into a network. This microfibrillar network acts as a platform or scaffold for the assembly of elastic fibers, which enable the skin, ligaments, and blood vessels to stretch. The microfibrillar network also provides support to the bones and to the tissues that support the nerves, muscles, and lenses of the eyes.

As part of the microfibrillar network, fibrillin-1 also regulates certain growth factor proteins. Growth factors are important proteins that help regulate cell processes such as the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement, and the self-destruction of cells (apoptosis). A particular growth factor called transforming growth factor beta (TGF-β) is stored within the microfibrillar network. When it is stored, TGF-β is turned off. Once it is released from the network, TGF-β is turned on and can activate important signaling pathways, including those involved in bone formation. By helping to regulate the availability of TGF-β, fibrillin-1 also helps regulate its activity.

Health Conditions Related to Genetic Changes

Acromicric dysplasia

Variants (also called mutations) in the FBN1 gene can cause acromicric dysplasia. This condition is characterized by severely short stature, short limbs, stiff joints, and distinctive facial features.

The FBN1 gene variants that cause acromicric dysplasia often lead to the substitution of one protein building block (amino acid) for another in a region of the fibrillin-1 protein called TGF-β binding-protein-like domain 5. As a result, the protein does not function properly, which disrupts the assembly and organization of microfibrils. Without enough microfibrils to properly store TGF-β, the growth factor is abnormally active. Although the mechanisms are unclear, these effects likely contribute to the features seen in people with acromicric dysplasia.

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Geleophysic dysplasia

Variants in the FBN1 gene can also cause geleophysic dysplasia, which is characterized by abnormalities of the bones, joints, skin, and heart. As with acromicric dysplasia, the FBN1 gene variants that cause geleophysic dysplasia typically lead to the substitution of one amino acid for another in the TGF-β binding-protein-like domain 5 region of the fibrillin-1 protein.

The altered version of fibrillin-1 disrupts the organization of the microfibrillar network within various tissues and causes the TGF-β growth factor to become abnormally active. While these changes are not completely understood, they likely contribute to the features seen in people with geleophysic dysplasia.

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Isolated ectopia lentis

Variants in the FBN1 gene have been found to cause isolated ectopia lentis. In people with this condition, the lens in one or both eyes is displaced (ectopic), which leads to vision problems. Most of the FBN1 gene variants that cause this condition lead to the substitution of one amino acid for another in fibrillin-1. As a result, cells produce a version of fibrillin-1 that does not function properly. This reduces the amount of fibrillin-1 that is available to form microfibrils. With fewer microfibrils to anchor the lens in its correct position, the lens is displaced, leading to the vision problems found in people with isolated ectopia lentis.

Ectopia lentis is classified as isolated when it occurs alone, without signs and symptoms that affect other body systems. However, some people with an FBN1 gene variant who initially receive a diagnosis of isolated ectopia lentis develop additional features that are similar to those seen in people with Marfan syndrome. This includes abnormalities of the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). In these cases, the diagnosis may change from isolated ectopia lentis to Marfan syndrome.

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Marfan syndrome

Over a thousand variants in the FBN1 gene can cause Marfan syndrome, a disorder that affects the connective tissues that support the body's joints and organs. Abnormalities in connective tissues lead to the heart problems, eye problems, and skeletal problems seen in people with this disorder. Affected individuals are usually tall and slender with elongated fingers and toes.

The variants that are associated with Marfan syndrome cause cells to produce a version of fibrillin-1 that does not function properly. This leads to a severe reduction in the amount of fibrillin-1 that is available to form microfibrils, which affects the tissue’s ability to stretch. In addition, fewer microfibrils are available to bind to growth factors, which causes some growth factors to become overly active. These changes lead to the overgrowth and instability of tissues seen in people with Marfan syndrome.

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Weill-Marchesani syndrome

Variants in the FBN1 gene have also been identified in people with Weill-Marchesani syndrome. Some of these variants cause cells to produce an unstable version of fibrillin-1. The unstable protein likely interferes with the assembly of microfibrils. Disruption of the microfibrillar network weakens connective tissue, which leads to the eye, heart, and skeletal abnormalities that are associated with Weill-Marchesani syndrome.

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Familial thoracic aortic aneurysm and dissection

MedlinePlus Genetics provides information about Familial thoracic aortic aneurysm and dissection

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Other disorders

Variants in the FBN1 gene can also cause a condition called stiff skin syndrome. This condition is characterized by very hard, thick skin that covers most of the body. The abnormal skin restricts movement and can lead to joint deformities called contractures, which further impair joint mobility. The signs and symptoms of stiff skin syndrome usually become apparent in infancy to mid-childhood.

Variants in the FBN1 gene can cause another condition called MASS phenotype. This condition involves abnormalities in several parts of the body, including the mitral valve (one of the valves that controls blood flow through the heart), the aorta (a large blood vessel that distributes blood from the heart to the rest of the body), the skeleton, and the skin. Many of the signs and symptoms seen in people with MASS phenotype overlap with those seen in people with Marfan syndrome. However, people with MASS phenotype do not have ectopia lentis, and the aortic problems tend to be milder than those seen in people with Marfan syndrome. 

FBN1 gene variants can also cause Marfan lipodystrophy syndrome, which is characterized by extremely flexible joints, elongated fingers and toes, and a loss of fatty tissue (lipodystrophy) underneath the skin. Affected individuals may also have a combination of facial features that gives them the appearance of aging prematurely (progeroid appearance), particularly in infancy. Though affected individuals share some signs and symptoms with people with Marfan syndrome, Marfan lipodystrophy syndrome and Marfan syndrome are considered separate disorders.

Other Names for This Gene

  • asprosin
  • Marfan syndrome
  • MASS
  • OCTD
  • SGS

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

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