FGFR1 gene

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.