Fibroblast growth factor receptor mutations

Definition

Fibroblast growth factor receptors (FGFRs) are a family of proteins specialized in growth inhibition. Mutations in these molecules lead to various genetic disorders involving short stature and/or premature fusion of the bones of the skull. There are at least four known FGFRs (FGFR1, FGFR2, FGFR3, FGFR4).

Description

As a group, FGFRs are very similar to each other in their structure and function. All are transmembrane proteins composed of three distinct parts. A binding site on the exterior of the cell membrane, an active site on the interior of the cell membrane, and a connecting section spanning the cell membrane and joining the inner and outer components.

Fibroblast growth factors (FGFs) attach to the binding site of extracellular portion of the FGFR protein. There are at least 17 known FGFs that bind and interact with FGFRs. Two FGFs must first bind with each other and, as a pair, are able to fit into the FGFR binding site forming an FGF/FGFR complex. FGF pairing and FGF/FGFR binding is non-specific, with any two FGFs coupling and binding any FGFR.

When the binding site is empty and no FGF is bound, the FGFR is inactive and cellular growth continues unchecked. When an FGF pair binds, the FGF/FGFR complex sends a signal that travels the length of the FGFR protein, resulting in the stimulation of the active site on the inside of the cell membrane.

The active site of the FGFR stimulates molecules within the cell through the biochemical process of phosphorylation. Each activated molecule goes on to affect another molecule, thereby propagating the original signal and, much like the domino effect, a cascade of events is triggered. The process continues, molecule by molecule, until the signal reaches the nucleus of the cell, ultimately resulting in the inhibition of cell growth.

Although highly recognized in the process of growth restriction, FGFRs are also thought to be involved in a wide variety of biological processes including migration of cells during embryo development, blood vessel growth, wound healing, cell death, and cancer .

Genes

A different gene codes for each of the four types of FGFR proteins (Table 1). Genes are the genetic material passed down from generation to generation that tell a person's body how to work and how to grow. Genes are packaged into chromosomes , with hundreds of genes on each chromosome. Individual cells contain 46 chromosomes, which may be matched into 23 pairs. One of each pair is inherited from the egg of the mother and one of each pair is inherited from the sperm of the father.

A mutation, meaning a change in an FGFR gene, also changes the structure of the FGFR protein, which then affects the protein's function. Most FGFR gene mutations are thought to cause the protein receptors to become overly active. These defective receptors continuously start the activation cascade independent of FGF

binding. This causes a strong slowing-down effect on growth, which is readily observed in the symptoms of affected individuals. Common features of the disease include abnormalities of the limbs, skin, head, and face.

Inheritance

Approximately ten genetic disorders have been linked to abnormal FGFRs. All FGFR-related syndromes are autosomal dominant. That is, although individuals inherit two copies of each gene FGFR gene, only one copy must be mutated for a person to be affected with a disorder. Some individuals with an FGFR-related disorder have a parent affected by the same disease, in which case the disease is said to be familial. Other individuals are the first person in their family to be affected. These cases are considered sporadic, meaning they arose from a new mutation in the affected person's DNA .

Whether familial or sporadic, all affected individuals have a 50% chance of passing on the disease to a child in any future pregnancy. The overall risk for a pregnancy can change if an affected person has a child with an individual affected by the same disease.

Prenatal testing

Prenatal testing is available for all of the FGFR-associated syndromes. Some cases are diagnosed based on clinical presentation, while others are diagnosed by DNA mutation analysis. Chorionic villus sampling (CVS) or amniocentesis may be used when there is a known familial mutation. If there is no family history of FGFR-related disease, but prenatal examination by ultrasound gives rise to concern, prognosis and diagnosis are traditionally based on clinical findings after birth.

Disease causing mutations

Syndromes involving FGFR gene mutations fall into two categories. The first category includes four disorders of short stature, all caused by mutations in the FGFR3 gene. The second category includes six syndromes involving skull malformations (craniosynostosis ), all caused by mutations in the FGFR1, FGFR2, or FGFR3

genes. As of 2001, there have been no disease-causing mutations reported in the FGFR4 gene.

Dwarfism

FGFR-related dwarfism disorders are all due to abnormal FGFR3 function (Table 2). Mutations in the FGFR3 gene are among the most common mutations in the human genome.

Achondroplasia was the first disease associated with FGFRs. It is the most common form of inherited disproportionate short stature with an incidence of one in 15,000 to one in 40,000 live births. Over 80% of cases of achondroplasia are sporadic, with a strong link to advanced paternal age.

Achondroplasia is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head, and characteristic facial features. Intelligence and life span are usually normal, although there is an increased risk of death in infancy from compression of the spinal cord and/or upper airway obstruction.

Hypochondroplasia is a form of short-limbed dwarfism also caused by a mutation in the FGFR3 gene. Although it appears clinically as a mild form of dwarfism, hypochondroplasia is caused by unique mutations in the FGFR3 gene, different than those that cause achondroplasia.

Thanatophoric dysplasia Types I and II and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) dysplasia are the most severe forms of FGFR-related dwarfism. Both types of thanatophoric dysplasia are fatal with death occurring before birth or during early infancy. As of 2001 there have been only three reported cases of SADDAN dysplasia. Although it is much like thanatophoric dysplasia in its presentation, affected individuals survive past infancy. Affected individuals are severely affected both mentally and physically. Both SADDAN dysplasia and thanatophoric dysplasiaa Types I and II have their own distinct FGFR3 gene mutations.

Craniosynostosis

Craniosynostosis is the hallmark feature of the second subset of disorders caused by FGFR gene mutations (Table 3). Craniosynostosis is the premature fusion of some or all of the bones of the skull. During normal development the bones of the skull do not completely fuse until the first to second year of life. This allows for passage through the narrow birth canal at delivery and for maximum brain growth during early developmental years.

There are over 150 genetic disorders that involve craniosynostosis that are not related to FGFR mutations. The collective incidence of all forms of craniosynostosis is 1/2000–1/2500 live births.

As of 2001, there are six craniosynotosis syndromes thought to be FGFR-related. All six display some form of craniosynostosis, distinctive facial features, and hand and foot deformations. Syndromes range from severe (neonatal death) to mild (no clinical manifestations). The characteristic facial features observed include underdevelopment of the midface, protruding eyes, down-slanting eyes, small beaked nose, protruding jaw (prognathism), and eyes that are unusually far apart (hypertelorism). Hand and foot anomalies are distinct for each syndrome and are sometimes used to distinguish between the disorders.

Future

Although the FGFR-related syndromes have been well-characterized, scientists continue to face some puzzling questions. It has been observed that identical FGFR gene mutations may result in two or more clinically distinct disorders, meaning with different symptoms. For example, a single mutation in the FGFR1 gene has been shown to result in Pfeiffer syndrome . The same mutation in the FGFR2 gene leads to Apert syndrome , while

the equivalent mutation in the FGFR3 gene produces Muenke craniosynostosis. Likewise, a single mutation in the FGFR2 gene may lead to any of the Crouzon, Pfeiffer, or Jackson-Weiss syndromes. The mechanism by which a particular mutation may lead to multiple different genetic disorders is not clearly understood.

Resources

BOOKS

Jorde, Lynne B., et al. Medical Genetics. St. Louis: Mosby, 1999.

PERIODICALS

Burke, David, et al. "Fibroblast Grown Factor Receptors: Lessons From the Genes." Trends in Biochemical Science (February 1998): 59-62.

Vajo, Z., et al. "The Molecular and Genetic Basis of Fibroblast Growth Factor Receptor 3 Disorders: The Achondroplasia Family of Skeletal Dysplasias, Muenke Craniosynostosis, and Crouzon Syndrome with Acanthosis Nigricans." Endocrine Reviews (February 2000): 23-39.

Webster, M. K., and D. J. Donoghue. "FGFR Activation in Skeletal Disorders: Too Much of a Good Thing." Trends in Genetics (May 1997): 178-182.

WEBSITES

GeneClinics.<http://www.geneclinics.org>.

Little People Online.<http://www.lpaonline.org>.

Online Inheritance of Man.<http://www3.ncbi.nlm.nih.gov/Omim>.

Java Olympia Solis, MS