FBN1

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 this matrix, fibrillin-1 binds to other molecules of fibrillin-1 and other proteins to form threadlike filaments called microfibrils. Microfibrils become part of elastic fibers, which enable the skin, ligaments, and blood vessels to stretch. Microfibrils also contribute to more rigid tissues that support the lens of the eye, nerves, and muscles. Additionally, microfibrils hold certain growth factors called transforming growth factor-beta (TGF-beta) proteins, which keeps them inactive. When released from microfibrils, TGF-beta growth factors are activated and affect the growth and repair of tissues throughout the body.

Marfan syndrome - caused by mutations in the FBN1 gene

Researchers have identified more than 600 FBN1 mutations that cause Marfan syndrome. More than 60 percent of these mutations change one of the protein building blocks (amino acids) used to make fibrillin-1. The remaining FBN1 mutations produce an abnormally small fibrillin-1 protein that cannot function properly. FBN1 mutations reduce the amount of fibrillin-1 produced by the cell, alter the structure or stability of fibrillin-1, or impair the transport of fibrillin-1 out of the cell. As a result, the amount of fibrillin-1 available to form microfibrils is severely reduced. Decreased microfibril formation probably weakens the elastic fibers and causes overactivation of TGF-beta growth factors, which leads to the signs and symptoms of Marfan syndrome.

Weill-Marchesani syndrome - caused by mutations in the FBN1 gene

A mutation in the FBN1 gene has also been identified in one family with Weill-Marchesani syndrome. This mutation deletes part of the gene, leading to the production of an unstable version of the fibrillin-1 protein. The unstable protein likely interferes with the assembly of microfibrils. Abnormal microfibrils weaken connective tissue, which causes the eye, heart, and skeletal abnormalities associated with Weill-Marchesani syndrome.

other disorders - caused by mutations in the FBN1 gene

Mutations in the FBN1 gene cause other disorders known as type 1 fibrillinopathies. Fibrillinopathies are disorders involving a deficiency of fibrillin proteins. Although Marfan syndrome is the most common type 1 fibrillinopathy, FBN1 mutations also cause a spectrum of disorders that vary in the age of onset and severity of symptoms. Some FBN1 mutations cause an adult-onset disorder called isolated ectopia lentis, in which dislocation of the lens of the eye causes vision problems. Other FBN1 mutations can cause an early-onset disorder known as Shprintzen-Goldberg craniosynostosis syndrome. The features of this syndrome are quite variable, but the main characteristics include premature fusion of certain bones of the skull (craniosynostosis) that affects the shape of the head and face; heart defects; long, slender fingers and toes (arachnodactyly); a build up of fluid in the brain (hydrocephalus); and intellectual disability.

In rare instances, another condition, MASS syndrome, is caused by the addition of a small amount of DNA to the FBN1 gene. MASS syndrome involves abnormalities in several structures, 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.