Normal Function
The FGFR1 gene provides instructions for making a protein called fibroblast growth factor receptor 1 (FGFR1). This protein is one of four fibroblast growth factor receptors, which are a family of 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 sticks out 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 on the outside of the cell, it starts a series of chemical reactions inside the cell that tell the cell to undergo certain changes or to learn new functions. This signaling is thought to play an important role in the development and growth of several parts of the body, including the brain, the bones in the head and face (craniofacial bones), the bones in the hands and feet, and the long bones in the arms and legs.
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, the signals passed through this protein appear 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 and testes. FGFR1 also appears to play a role in the processing of smells by a specialized group of neurons (olfactory neurons).
Health Conditions Related to Genetic Changes
8p11 myeloproliferative syndrome
The FGFR1 gene is involved in a type of blood cancer called 8p11 myeloproliferative syndrome. This condition is characterized by an increase in the number of white blood cells (myeloproliferative disorder) and the development of lymphoma, a blood-related cancer that causes tumors to form in the lymph nodes. The myeloproliferative disorder usually develops into another form of blood cancer called acute myeloid leukemia. 8p11 myeloproliferative syndrome is caused by 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 commonly fused gene is ZMYM2 on chromosome 13. These translocations are found only in cancer cells.
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.
Encephalocraniocutaneous lipomatosis
A few variants (also called mutations) in the FGFR1 gene have been identified in people with encephalocraniocutaneous lipomatosis (ECCL), a rare condition characterized by the growth of noncancerous tumors and other abnormalities in the brain, eyes, and skin. The variants that cause ECCL are not inherited from a parent; they arise randomly in one cell during the early stages of development before birth. As cells continue to grow and divide, some cells will have the variant and other cells will not. This mixture of cells with and without a genetic variant is known as mosaicism.
The FGFR1 gene variants associated with ECCL change single protein building blocks (amino acids) in the FGFR1 protein. These variants are described as "gain-of-function" variants because they overactivate the receptor, triggering abnormal signaling that affects cell growth and division. Researchers are studying how these changes in signaling lead to tumor growth and the other features of ECCL.
Hartsfield syndrome
Variants in the FGFR1 gene have been identified in people with Hartsfield syndrome. People with this rare condition have an abnormality in their brain development called holoprosencephaly. They also have a malformation of the hands and feet called split hand/foot.
Some of these variants affect one of the two copies of the FGFR1 gene in each cell. In other cases, variants occur in both copies of the FGFR1 gene.
All of the variants associated with Hartsfield syndrome greatly reduce or eliminate the function of the FGFR1 protein, including its ability to attach (bind) to FGFs. As a result, the receptor is unable to transmit signals properly, which impairs many aspects of normal development. It is unclear how these changes lead specifically to holoprosencephaly and split hand/foot in people with Hartsfield syndrome.
Kallmann syndrome
Many FGFR1 gene variants have been found to cause Kallmann syndrome, a disorder characterized by the combination of hypogonadotropic hypogonadism (a condition that affects the production of hormones that direct sexual development) and an impaired sense of smell. This condition can also affect other body systems, and its features vary among affected individuals. Researchers estimate that variants in the FGFR1 gene account for about 10 percent of all cases of Kallmann syndrome.
The FGFR1 gene variants that cause Kallmann syndrome change single amino acids in the FGFR1 protein or result in the production of an abnormally small, nonfunctional version of the protein. Because these variants reduce or eliminate the function of FGFR1, preventing it from transmitting signals properly, they are described as "loss-of-function" variants. Studies suggest that a shortage of functional FGFR1 disrupts the migration and survival of olfactory neurons and GnRH-producing neurons in the developing brain. People with Kallmann syndrome may have a poor sense of smell or no sense of smell at all because their olfactory nerve cells do not extend to the olfactory bulb. In addition, the misplacement or premature loss of GnRH-producing neurons prevents the production of sex hormones. This can interfere with normal sexual development, and people with this condition may experience puberty later than normal or not at all.
Some people with Kallmann syndrome caused by FGFR1 gene variants have additional features, such as a split in the lip (cleft lip) with an opening in the roof of the mouth (a cleft palate), abnormal tooth development, and abnormalities of the hands and feet. It is unclear how variants in the FGFR1 gene lead to these other signs and symptoms. Because these features vary among individuals, researchers suspect that other genetic and environmental factors may be involved. Some affected individuals have variants in one of several other genes in addition to FGFR1, and these genetic changes may contribute to the varied features of the condition.
Osteoglophonic dysplasia
A few variants in the FGFR1 gene are known to cause a rare condition called osteoglophonic dysplasia. People with this condition show abnormal bone growth that leads to craniofacial abnormalities, including the premature fusion of certain bones in the skull (craniosynostosis). They may also lack teeth, or their teeth may not appear until later in their development. Small areas in the long bones of their arms and legs may appear hollow on an x-ray, and they may have short stature.
FGFR1 gene variants that cause osteoglophonic dysplasia will a change single amino acid in the FGFR1 protein sequence. These FGFR1 gene variants are described as "gain-of-function" variants because they abnormally increase FGFR1 signaling. The altered FGFR1 protein promotes premature fusion of bones in the skull and disrupts the regulation of bone growth in the arms and legs, leading to the craniofacial abnormalities and shortened limbs seen in people with osteoglophonic dysplasia. This overactive FGFR1 protein can also increase the release (secretion) of a bone hormone called FGF23, resulting in abnormally high amounts of phosphate in the urine and low levels of phosphate in the blood. This further impairs bone health and growth in individuals with osteoglophonic dysplasia.
Pfeiffer syndrome
Other "gain-of-function" variants in the FGFR1 gene can cause Pfeiffer syndrome. This condition is characterized by craniosynostosis, which leads to a misshapen head and distinctive facial features. Affected individuals also have hand and foot abnormalities. The FGFR1 gene variants that cause this condition change single amino acids in the FGFR1 protein. The altered FGFR1 protein appears to prolong signaling, which promotes early fusion of the skull bones and affects the development of bones in the hands and feet.
Other disorders
Several variants in the FGFR1 gene have been found to cause a form of hypogonadotropic hypogonadism that occurs without an impaired sense of smell. This condition is often called normosmic isolated hypogonadotropic hypogonadism (nIHH). Like the FGFR1 gene variants that cause Kallmann syndrome (described above), these variants reduce or eliminate the function of the FGFR1 protein, preventing it from transmitting signals properly.
A shortage of functional FGFR1 disrupts the migration of GnRH-producing nerve cells in the developing brain, which affects the production of sex hormones and can delay or prevent puberty. It is unclear why some FGFR1 gene variants affect the sense of smell (resulting in Kallmann syndrome) and others do not (resulting in nIHH). A few variants have been found to cause Kallmann syndrome in some people and nIHH in others.
Other cancers
Changes involving the FGFR1 gene have been found in people with certain cancers. These genetic changes are somatic, which means they are not inherited but instead occur in the cells that give rise to the tumor. Gene amplification, which results in an abnormally large number of copies of the FGFR1 gene, occurs in several forms of cancer. These include some cancers of the lung, esophagus, breast, and oral cavity. Additionally, variants that change single amino acids in the FGFR1 gene have been identified in several types of brain tumor.
Studies suggest that the genetic changes in FGFR1 that are associated with cancer abnormally increase the activity of the FGFR1 protein and enhance its ability to trigger chemical reactions within the cell. The resulting uncontrolled signaling can promote continuous cell growth and division, which is a hallmark of cancer. Amplification of the FGFR1 gene has been associated with a poorer prognosis for people with some cancers and an increased likelihood that the tumor will spread (metastasize) to other parts of the body.
Rearrangements of genetic material involving the FGFR1 gene are associated with the development of a condition called tumor-induced osteomalacia. This condition is a set of signs and symptoms that arise in response to the presence of a tumor in the body. The features of tumor-induced osteomalacia are a softening of the bones (osteomalacia), muscle weakness, bone pain, and fractures. They develop because of a noncancerous tumor called a phosphaturic mesenchymal tumor (PMT).The rearrangements cause the FGFR1 gene to become fused with another gene, most commonly the FN1 gene. The protein produced from the FN1-FGFR1 fusion gene is highly active (expressed) and can bind to other proteins. This fusion gene is found in 60 percent of PMTs.PMTs often lead to low levels of vitamin D and phosphate in the blood (hypophosphatemia), resulting in the problems with bone health seen in people with tumor-induced osteomalacia.
Other Names for This Gene
- BFGFR
- C-FGR
- CD331
- CEK
- FGFR1_HUMAN
- fibroblast growth factor receptor 1 (fms-related tyrosine kinase 2, Pfeiffer syndrome)
- FLG
- FLJ14326
- FLT2
- FMS-like gene
- FMS-like tyrosine kinase 2
- heparin-binding growth factor receptor 1
- hydroxyaryl-protein kinase
- KAL2
- N-SAM tyrosine kinase
- protein-tyrosine kinase
- tyrosyl protein kinase
Genomic Location
The
FGFR1 gene is found on chromosome 8.