FGFR1

This gene encodes a protein that plays a role in cell division, cell growth, and the formation of blood vessels and embryos. Mutations can cause many different disorders and cancer (R).

The FGFR1 gene provides instructions for making a protein called fibroblast growth factor receptor 1. This protein is one of four fibroblast growth factor receptors, which are related proteins that are involved in 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 is inside the cell and the other end projects from the outer surface of the cell. This positioning allows the FGFR1 protein to interact with other proteins called fibroblast growth factors (FGFs) outside the cell and to receive signals that help the cell respond to its environment. When an FGF attaches 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. This signaling is thought to play an important role in the development and growth of several parts of the body, including the brain, bones of the head and face (craniofacial bones), bones in the hands and feet, and the long bones in the arms and legs.

Signaling through the FGFR1 protein plays a critical role in the formation, survival, and movement (migration) of nerve cells (neurons) in several areas of in the brain. In particular, this signaling appears to be essential for neurons that produce a hormone called gonadotropin-releasing hormone (GnRH). GnRH controls the production of several other hormones that direct sexual development before birth and during puberty. These hormones are important for the normal function of the ovaries in women and the testes in men. FGFR1 also appears to play a role in a group of nerve cells that are specialized to process smells (olfactory neurons). These neurons migrate from the developing nose to a structure at the front of the brain called the olfactory bulb, which is critical for the perception of odors.

     8p11 myeloproliferative syndrome The FGFR1 gene is involved in a type of blood cancer called 8p11 myeloproliferative syndrome. This condition is characterized by an increased number of white blood cells (myeloproliferative disorder) and the development of lymphoma, a blood-related cancer that causes tumor formation in the lymph nodes. The myeloproliferative disorder usually develops into another form of blood cancer called acute myeloid leukemia. 8p11 myeloproliferative syndrome results from a rearrangement (translocation) of genetic material between chromosome 8 and another chromosome, which fuses part of the FGFR1 gene with part of another gene from the other chromosome. The most common partner gene is ZMYM2 on chromosome 13. These translocations are found only in cancer cells. Regardless of the partner gene, the protein produced from the fused gene turns on FGFR1 signaling without the need for stimulation from growth factors. The uncontrolled signaling promotes continuous cell growth and division, leading to cancer. Kallmann syndrome Researchers have identified more than 40 FGFR1 gene mutations that cause Kallmann syndrome type 2, which is a condition characterized by delayed or absent puberty and an impaired sense of smell. 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 gene 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 gene 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. osteoglophonic dysplasia Several mutations in the FGFR1 gene can cause a rare condition called osteoglophonic dysplasia. This condition is characterized by abnormal bone growth that leads to head and face (craniofacial) abnormalities and dwarfism. FGFR1 gene mutations that cause osteoglophonic dysplasia change single amino acids 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, leading to craniofacial abnormalities and shortened limbs. Because the FGFR1 gene mutations that cause osteoglophonic dysplasia abnormally enhance FGFR1 signaling, they are described as “gain-of-function” mutations. Pfeiffer syndrome Another gain-of-function mutation in the FGFR1 gene causes type 1 Pfeiffer syndrome. This condition is characterized by premature fusion of certain bones in the skull (craniosynostosis), which leads to a misshapen head and distinctive facial features. Affected individuals also have hand and foot abnormalities. The FGFR1 gene mutation that causes this condition changes a single amino acid in the FGFR1 protein: 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 early fusion of the skull bones and affects the development of bones in the hands and feet. cancers 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, cell movement, and the development of new blood vessels 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 gene expression has also been found in pancreatic, esophageal, ovarian, testicular, breast, and head and neck cancers.

     The FGFR1 gene provides instructions for making a protein called fibroblast growth factor receptor 1. This protein is one of four 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 other proteins called fibroblast growth factors outside the cell and to receive signals that help the cell respond to its environment. When a fibroblast growth factor attaches 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.