FGFR1

The FGFR1 gene provides instructions for making a protein called fibroblast growth factor receptor 1. This protein is one of several fibroblast growth factor receptors, which are related proteins that are involved in important processes such as cell division, regulation of cell growth and maturation, formation of blood vessels, wound healing, and embryonic development.

The FGFR1 protein spans the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This positioning allows the FGFR1 protein to interact with specific growth factors outside the cell and to receive signals that help the cell respond to its environment. When growth factors attach to the FGFR1 protein, the receptor triggers a cascade of chemical reactions inside the cell that instruct the cell to undergo certain changes, such as maturing to take on specialized functions. The FGFR1 protein is thought to play an important role in the development of the nervous system. This protein may also help regulate the growth of long bones, such as the large bones in the arms and legs.

Kallmann syndrome - caused by mutations in the FGFR1 gene

Researchers have identified more than 40 FGFR1 mutations that cause Kallmann syndrome type 2. These mutations change single protein building blocks (amino acids) in the FGFR1 protein or result in the production of an abnormally small, nonfunctional version of the protein. Because these mutations prevent the FGFR1 protein from transmitting signals properly, they are described as "loss of function" mutations.

During brain development, the altered FGFR1 protein disrupts the formation and movement (migration) of nerve cells that process smells (olfactory neurons). These neurons must come together into a bundle called the olfactory bulb for a person to perceive odors. Problems with the migration of nerve cells into the olfactory bulb underlie the impaired sense of smell in people with Kallmann syndrome. FGFR1 mutations also disrupt the migration of nerve cells that produce gonadotropin-releasing hormone (GnRH) in the developing brain. GnRH controls the production of several other hormones that direct sexual development before birth and during puberty. An altered FGFR1 protein prevents the normal migration of GnRH-producing nerve cells in the brain, which interferes with sexual development and causes puberty to be delayed or absent.

It is unclear how FGFR1 mutations lead to other signs and symptoms of Kallmann syndrome, including an opening in the roof of the mouth (a cleft palate) and abnormal tooth development. Because the features of this condition vary among individuals, researchers suspect that other genetic and environmental factors may be involved.

Pfeiffer syndrome - caused by mutations in the FGFR1 gene

Type 1 Pfeiffer syndrome is caused by a mutation in the FGFR1 gene that changes a single amino acid in the FGFR1 protein. As a result of this mutation, the amino acid proline is replaced with the amino acid arginine at protein position 252 (written as Pro252Arg). The altered FGFR1 protein appears to cause prolonged signaling, which promotes premature fusion of the skull bones and affects the development of bones in the hands and feet. Because the Pro252Arg mutation abnormally enhances FGFR1 signaling, it is described as a "gain of function" mutation.

cancers - associated with the FGFR1 gene

Alterations in the activity (expression) of the FGFR1 gene are associated with certain cancers. The altered gene expression may enhance several cancer-related events such as cell division (proliferation), cell movement, and the development of new blood vessels (angiogenesis) that nourish a growing tumor.

The FGFR1 gene is abnormally active (overexpressed) in certain types of stomach and prostate cancers. This amplification is associated with tumor progression and a poorer outcome. Altered FGFR1 expression has also been found in pancreatic, esophageal, ovarian, testicular, breast, and head and neck cancers.

The FGFR1 gene is also involved in a type of blood cancer called 8p11 myeloproliferative syndrome. This type of cancer can result from a rearrangement (translocation) of genetic material between chromosome 8 and another chromosome. This translocation occurs only in cancer cells. It fuses part of the FGFR1 gene on chromosome 8 with part of another gene from the other chromosome. The protein produced from the fused gene overactivates FGFR1 signaling, which promotes the uncontrolled growth and division of cancer cells.

other disorders - caused by mutations in the FGFR1 gene

Several gain-of-function mutations in the FGFR1 gene can cause a rare condition called osteoglophonic dysplasia. This condition is characterized by the premature fusion of certain bones in the skull (craniosynostosis) and shortened limbs due to abnormal bone growth in the arms and legs. Craniosynostosis affects the shape of the head and face; among other features, people with this disorder have a prominent forehead and a short nose. FGFR1 mutations that cause osteoglophonic dysplasia change a single building block (amino acid) in the FGFR1 protein. The altered FGFR1 protein appears to cause prolonged signaling, which promotes premature fusion of bones in the skull and disrupts the regulation of bone growth in the arms and legs.