FGFR3

The FGFR3 gene provides instructions for making a protein called fibroblast growth factor receptor 3. This protein is part of a family of fibroblast growth factor receptors that share similar structures and functions. These proteins play a role in several important cellular processes, including regulation of cell growth and division, determination of cell type, formation of blood vessels, wound healing, and embryo development.

The FGFR3 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 of the protein allows it to interact with specific growth factors outside the cell and to receive signals that control growth and development. When these growth factors attach to the FGFR3 protein, the protein is turned on (activated), which 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.

Several different versions (isoforms) of the FGFR3 protein are produced from the FGFR3 gene. The different isoforms are found in different tissues of the body and they interact with different growth factors. Several different isoforms are found in the cells that form bones. Researchers believe that the FGFR3 protein in bone cells regulates bone growth by limiting the formation of bone from cartilage (a process called ossification), particularly in the long bones. One particular isoform of the FGFR3 protein is found specifically in cells that line the surfaces of the body (epithelial cells), including the cells that form the outermost layer of skin, called the epidermis. The specific function of the FGFR3 protein in skin cells is unclear, but research shows that the protein plays a role in regulating cell growth and division.

achondroplasia - caused by mutations in the FGFR3 gene

Two mutations in the FGFR3 gene cause more than 99 percent of cases of achondroplasia. Both mutations lead to the same change in building blocks (amino acids) that make up the fibroblast growth factor receptor 3 protein. Specifically, the amino acid glycine is replaced with the amino acid arginine at protein position 380 (written as Gly380Arg or G380R). Researchers believe that this genetic change causes the receptor to be overly active, which leads to the disturbances in bone growth seen with this disorder.

Crouzonodermoskeletal syndrome - caused by mutations in the FGFR3 gene

A single FGFR3 mutation has been identified in people with Crouzonodermoskeletal syndrome. This genetic change replaces the amino acid alanine with the amino acid glutamic acid at position 391 of the fibroblast growth factor receptor 3 protein (written as Ala391Glu or A391E). Researchers have not determined how this mutation leads to the signs and symptoms of this disorder, but the altered receptor appears to disrupt the normal growth of skull bones and affect skin pigmentation.

hypochondroplasia - caused by mutations in the FGFR3 gene

Several mutations in the FGFR3 gene have been identified in people with hypochondroplasia. Many cases are caused by one of two specific FGFR3 mutations, both of which lead to the same change in amino acids in the fibroblast growth factor receptor 3 protein. Specifically, the amino acid asparagine is replaced with the amino acid lysine at protein position 540 (written as Asn540Lys or N540K). Other FGFR3 mutations probably cause a small number of cases of hypochondroplasia. Although the effects of these mutations have not been explained, they probably cause the receptor to be mildly overactivated, which leads to the disturbances in bone growth seen with this disorder.

Muenke syndrome - caused by mutations in the FGFR3 gene

A single mutation in the FGFR3 gene has been shown to cause Muenke syndrome. This change substitutes the amino acid arginine for the amino acid proline at position 250 in the fibroblast growth factor receptor 3 protein (written as Pro250Arg or P250R). This mutation results in the production of a receptor that is overly active, which allows the bones of the skull to fuse before they should.

The Pro250Arg mutation has also been identified in some people with apparently isolated coronal craniosynostosis. This condition is characterized by a premature fusion of the growth line that runs across the top of the head from ear to ear (the coronal suture). People with isolated coronal craniosynostosis do not have the other features of Muenke syndrome, such as hearing loss, hand and foot abnormalities, or developmental delay.

SADDAN - caused by mutations in the FGFR3 gene

One mutation in the FGFR3 gene has been identified in people with SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans). This genetic change substitutes the amino acid methionine for the amino acid lysine at position 650 of the fibroblast growth factor receptor 3 protein (written as Lys650Met or K650M). Researchers believe that this mutation strongly overactivates the FGFR3 protein, which leads to severe problems with bone growth. It remains uncertain how the mutation disrupts brain development or causes acanthosis nigricans (a skin disorder characterized by thick, dark, velvety skin).

thanatophoric dysplasia - caused by mutations in the FGFR3 gene

At least 10 mutations in the FGFR3 gene have been identified in people with thanatophoric dysplasia type I. Most of these mutations change a single amino acid in the fibroblast growth factor receptor 3 protein. The most common mutation substitutes the amino acid cysteine for the amino acid arginine at protein position 248 (written as Arg248Cys or R248C). Other mutations cause the protein to be longer than normal.

Only one mutation has been shown to cause thanatophoric dysplasia type II. This mutation replaces the amino acid lysine with the amino acid glutamic acid at position 650 of the fibroblast growth factor receptor 3 protein (written as Lys650Glu or K650E). This change affects a different part of the FGFR3 protein than the mutations that cause thanatophoric dysplasia type I.

The genetic changes responsible for both types of thanatophoric dysplasia cause the FGFR3 receptor to be overactivated, which leads to the severe problems with bone growth seen in these conditions. It is not known how FGFR3 mutations lead to the brain and skin abnormalities associated with thanatophoric dysplasia.

bladder cancer - associated with the FGFR3 gene

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic mutations in the FGFR3 gene are associated with some cases of bladder cancer. These mutations overactivate the fibroblast growth factor receptor 3 protein, which likely directs bladder cells to grow and divide abnormally. This uncontrolled cell division leads to the formation of a bladder tumor.

Several somatic mutations in the FGFR3 gene are associated with bladder cancer when they occur only in bladder cells. These same mutations cause the skeletal disorder thanatophoric dysplasia when they are inherited from a parent (and occur in all of the body's cells).

epidermal nevus - associated with the FGFR3 gene

Mutations in the FGFR3 gene have been found in approximately 30 percent of people with a certain type of epidermal nevus (plural: nevi). Specifically, FGFR3 gene mutations are associated with some keratinocytic epidermal nevi, which are abnormal skin growths that are composed of a particular type of skin cell called a keratinocyte. FGFR3 gene mutations have not been found in other types of epidermal nevi.

The most common FGFR3 gene mutation in epidermal nevi changes a single amino acid in the FGFR3 protein. The amino acid arginine is replaced with the amino acid cysteine at position 248 (written as Arg248Cys or R248C). This mutation creates a protein that is turned on without attachment of a growth factor, which means that the FGFR3 protein is constantly active. Cells with this FGFR3 gene mutation grow and divide more than normal cells. In addition, the mutated cells do not initiate a form of self-destruction called apoptosis as readily as normal cells. These effects result in overgrowth of skin cells, leading to epidermal nevi.

The FGFR3 gene mutations found in epidermal nevi are also seen in people with another skin abnormality called seborrheic keratosis and in people with thanatophoric dysplasia, Crouzonodermoskeletal syndrome, and SADDAN syndrome. However, unlike in the skeletal conditions, the mutations associated with epidermal nevi (and seborrheic keratoses) are somatic mutations, which means they occur in the body's cells after conception and are not inherited.

other disorders - caused by mutations in the FGFR3 gene

Mutations in the FGFR3 gene also cause platyspondylic lethal skeletal dysplasia, San Diego type. This skeletal disorder is characterized by severe problems with bone growth similar to thanatophoric dysplasia. Most mutations that cause this disorder change single amino acids in the FGFR3 protein. The altered protein is improperly folded and cannot be transported to the cell membrane. Instead, it accumulates within cartilage cells (chondrocytes) and forms clumps called inclusion bodies. The absence of normal FGFR3 signaling and the formation of inclusion bodies probably disrupt the normal development of bones, leading to the skeletal abnormalities characteristic of platyspondylic lethal skeletal dysplasia, San Diego type.

Mutations in the FGFR3 gene have also been found in 30 to 70 percent of people with seborrheic keratoses, which are small, dark, noncancerous (benign) tumors of the skin caused by overgrowth of skin cells. Seborrheic keratoses develop in adulthood and are seen in a majority of people older than age 50. The FGFR3 mutations associated with seborrheic keratosis are somatic mutations, which means they occur during a person's lifetime and are not inherited. At least nine FGFR3 gene mutations have been identified in people with seborrheic keratoses. These mutations change single amino acids in the FGFR3 protein. The mutated FGFR3 proteins are abnormally active, which results in the overgrowth of skin cells, leading to seborrheic keratosis. It has been suggested that the mutations involved in seborrheic keratosis may be caused by exposure to ultraviolet (UV) light.

other cancers - associated with the FGFR3 gene

In addition to bladder cancer, somatic mutations in the FGFR3 gene have been associated with a cancer of white blood cells (multiple myeloma) and cervical cancer. Some cases of multiple myeloma are related to a rearrangement of genetic material (a translocation) involving chromosome 14 and the region of chromosome 4 containing the FGFR3 gene. Mutations that have been associated with cervical cancer are changes in single DNA building blocks (base pairs) in the FGFR3 gene.

FGFR3 mutations that lead to multiple myeloma and cervical cancer are thought to overactivate the fibroblast growth factor receptor 3 protein in certain cells. The mutated receptor directs the cells to grow and divide in the absence of signals from outside the cell. This uncontrolled division can lead to the overgrowth of cancer cells.