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Human Forkhead-Box Gene Family

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Related terms
Background
Methods
Research
Implications
Limitations
Safety
Future research
Author information
Bibliography

Related Terms
  • Autoimmunity, cancer, chemiluminescence, colorimeter, congenital disorder, developmental biology, diabetes mellitus, dideoxynucleotide triphosphate, DNA sequencing, FISH, fluorescence in situ hybridization, forkhead-box domain, FOX genes, gene family, human genetics, human genome, IPEX syndrome, lymphedema-distichiasis syndrome, mass spectrometer, mutation, oncology, PCR, polymerase chain reaction, polymorphism, protein microarray, speech and language disorder, transcription factor.

Background
  • The human Forkhead-box (FOX) gene family is a set of genes which code for proteins called transcription factors, which play a critical role in directing the activity of many other genes. Transcription factors function by binding to specific regions of DNA and controlling how genes are transcribed. The FOX gene family consists of at least 43 members that have been further subdivided into class one and class two FOX proteins based on certain structural similarities. A letter and a number are used to identify the specific subfamily to which a particular gene belongs. Subfamilies are denoted by a letter (A through R) and the individual genes in these subfamilies are further designated by a number, e.g., FOXD4. The subfamilies A-G, I-L, and Q are grouped under class one while H and M-P are grouped under class two.
  • In general, a gene family comprises a group of genes related by sequence similarity. The genes belonging to the same family provide instructions for making proteins that have a similar function and structure. The classification of individual genes into families helps scientists to understand the structure and function of genes and how they evolved.
  • The FOX gene family provides instructions for making proteins that play a major role in the development/formation of many organs and tissues before birth. FOX proteins regulate particular gene activities in the eyes, lungs, brain, cardiovascular system (relating to heart/blood vessels), digestive system, immune system, and cell cycle. FOX genes also modulate a wide spectrum of biological processes.
  • The loss of function of FOX family genes due to mutation (a permanent variation in the DNA sequence of the gene) plays a key role in the pathogenesis (origin and development) of several diseases including diabetes mellitus, and cancer, as well as a number of other, congenital disorders (disorders present at birth).

Methods
  • General: The FOX gene family provides instructions for making proteins that play a major role in the development/formation of many organs and tissues during development. Mutations in genes of this family may lead to the development of any number of diseases or congenital malformations. For both these reasons, the FOX gene family is of intense scientific interest. To that end, a number of methods of genetic analysis have been employed to help identify FOX genes, their function, and how mutations affect the expression of FOX proteins and give rise to disease. Listed below are brief descriptions of a few of the relevant methods used in such genetic research.
  • Mass spectrometry: Structural information of the FOX family members may be generated using certain types of mass spectrometers, usually those with multiple analyzers, which are known as tandem mass spectrometers. Mass spectrometry (MS) is an analytical technique used for measuring the molecular mass of a sample, thereby helping to identify the chemical composition of a compound present in the sample. A mass spectrometer creates ions (charged particles) from molecules and analyzes those ions to provide information about the molecular weight/mass of the compound and its chemical structure. MS functions by breaking down a sample into ions which are then separated based on the charge and mass of the particles. The separated particles are later identified using a detector, a part of the mass spectrometer that measures and records the current produced when an ion hits a detecting surface. This procedure is useful for the identification of proteins and oligonucleotides (short segments of DNA).
  • Protein microarrays: Protein microarrays, or protein chips, are devices with different substances (proteins or DNA sequences) affixed to a solid substrate in a regular pattern which can bind target molecules for the purpose of rapid, parallel biochemical and genetic analysis. Each point in the affixed pattern corresponds to a particular target. By analyzing the pattern of binding, the target molecules present in a sample run through a microarray can be identified. This pattern may be detected by attaching targets with probes tagged with some kind of detectable signal molecule, such as a fluorescent dye.
  • Polymerase chain reaction (PCR): PCR is an efficient and sensitive enzymatic laboratory technique used to amplify (produce many compies) of a specific sequence of DNA. PCR uses specific oligonucleotide primers and the enzyme DNA polymerase to enable the reaction. Oligonucleotide primers are sequences of nucleotides, usually 20-50 bases long, that are complementary to a specific DNA sequence and which serve as a starting point for DNA replication. DNA polymerase is an enzyme that synthesizes new DNA strands using preexisting DNA strands as template. A radionucleotide is also often incorporated into the PCR product during the amplification process to allow for visualizing of the PCR product at a later stage.
  • DNA sequencing: DNA sequencing is a process by which the precise sequence of nucleotides from a sample of DNA is determined. The most well known method of DNA sequencing is likely Sanger's method (dideoxy or chain termination method).The initial step involves the extraction of high quality DNA from the sample of interest, followed by polymerase chain reaction (PCR) in the presence of fluorescent labeled dideoxynucleotide triphosphate (ddNTP). ddNTPs are synthetic or man-made nucleotides that are structurally somewhat different from the regular nucleotides found in DNA, and function as DNA chain terminators (stop signals) during the synthesis of a DNA sequence. The end reaction product is a set of DNA sequences differing in length by one nucleotide with the last nucleotide base in each sequence being the unique, fluorescent labeled ddNTP.
  • The reaction products are then electrophoresed. Electrophoresis is a technique that uses electrical current to separate and analyze proteins and DNA via differences in electrical charge. The separated DNA fragments are then paired with complementary sequence of DNA called probes. These probes are tagged with a dye that emits luminescence facilitating the easy detection of the target sequence. These fluorescent signals are analyzed by a computer, identifying the exact sequence of DNA. The whole process is automated and the resultant DNA sequence is compared with other sequences by various computer programs, allowing for the identification of mutations in the sample DNA sequence.
  • Conventional DNA sequencing is laborious, time consuming, and expensive, but with the development and improvement of automated DNA sequencers and newer detection methods, the technique has become much more efficient and cost-effective. Some advantages of direct DNA sequencing include the precise identification of the type, location, and context of each mutation in a particular DNA sequence.
  • Fluorescence in situ hybridization (FISH): FISH is a method that may be used to detect FOX gene mutations. To perform FISH, researchers first identify a specific region of a chromosome that they are interested in studying (for example, a region that contains a specific FOX gene). Cell lines made from blood, amniotic fluid, or bone marrow are commonly used for analysis. Then a probe is generated that can recognize and bind to the chromosomal region of interest. In FISH, the probes that researchers use are fluorescently labeled so that they emit a colored light if the chromosomal region of interest is present in a cell.

Research
  • General: Scientific study into the FOX gene family is ongoing. Listed below are some examples of FOX-related research.
  • Liver regeneration: The human liver is one of the few adult organs capable of completely regenerating itself in response to injury by releasing growth factors that stimulate reentry of terminally differentiated liver cells into the cell cycle. Terminal differentiated cells are those that are in the final stages of stem cells conversion to a specialized cell and are known to withdraw from the cell cycle at this stage. Growth factors are hormones produced by the body or obtained from food that promote growth and development by directing cell maturation and by mediating the maintenance and repair of tissues. FoxM1B has been detected in all proliferative cells that are actively dividing to produce new tissue and is closely related to the growth of hepatocytes (liver cells). Researchers have found that FoxM1B regulates genes that are essential for cell division and that reduced expression of FoxM1B leads to defects in cell division. Based on these findings, drugs that increase the expression of FoxM1B may help in regeneration of lost or damaged tissue.
  • Vaccination in multiple sclerosis: Multiple sclerosis (MS) is a chronic (long-term), progressive, degenerative disorder that affects nerve fibers in the brain and spinal cord. Multiple sclerosis is widely believed to be an autoimmune disease, a condition in which the immune system attacks components of the body as if they are foreign. It has been found that FOXP3 is associated with the regulation of autoimmune diseases and maintaining immune tolerance, and that FOXP3 expression is reduced in MS patients. Researchers are conducting studies with a vaccine using T-cell receptor (TCR) peptides that are commonly expressed by disease-causing T cells (a type of immune cell). TCR is located on the surface of T-cells and helps recognize antigens (foreign agents) in the body. A receptor is a protein on or protruding from the cell surface to which select chemicals can bind. Research has indicated that this vaccine stimulates the FOXP3 gene and may be helpful in treating this disorder.

Implications
  • General: The FOX gene family provides instructions for making proteins that play a major role in the development/formation of many organs and tissues during development. Mutations in genes of this family may lead to the development of any number of diseases or congenital malformations. For both these reasons, the FOX gene family is of intense scientific interest. Hence, identifying the expression profiles, mutations, proteins, and target genes of the FOX family may help in the development of new therapies to prevent and treat several human diseases. Some of the common disorders caused by mutations in the FOX genes are described below.
  • Congenital disorders: A congenital disorder is a condition that is present at birth. Most human congenital disorders are due to mutations in the FOX gene family, especially as a result of the FOXC1, FOXC2, FOXE1, FOXE3, FOXL2, FOXN1, FOXP2, and FOXP3 genes.
  • Cancer: The overexpression of the FOXA1 gene has been associated with cancers found in the lungs and esophagus, while mutations in FOXM1 have been suggested to cause pancreatic cancer.
  • Lymphedema-distichiasis syndrome: Mutations in the FOXC2 gene has been shown to cause lymphedema-distichiasis syndrome. This syndrome is a condition that affects the normal function of the lymphatic system, part of the body's immune system that helps in the production or transportation of fluids and immune cells throughout the body. People affected by this syndrome develop swelling or puffiness of the limbs (lymphedema) and also have extra eyelashes present at birth. The abnormal eyelashes may cause damage to the clear covering of the eye (cornea) and may result in blurred vision.
  • IPEX syndrome: Most mutations in the FOXP3 gene result in the development of immune dysregulation, polyendocrinopathy (the dysfunction of several hormone producing glands), enteropathy (intestinal diseases), or X-linked (IPEX) syndrome. The FOXP3 gene provides instructions for producing the forkhead box P3 (FOXP3) protein, which controls the activity of genes that are involved in regulating the immune system. This protein is essential for the production and normal function of immune cells (regulatory T cells/lymphocytes), which in turn play a key role in preventing the development of autoimmunity. Autoimmunity is a condition in which the body's immune system attacks its own tissues and organs. A mutation in FOXP3 gene may result in the development of IPEX syndrome, which involves the development of multiple autoimmune disorders in many different areas of the body, especially in the intestines (enteropathy), the skin, and hormone-producing (endocrine) glands. For example, individuals affected with IPEX syndrome develop type 1 diabetes mellitus, which is an autoimmune endocrine disorder involving the pancreas.
  • Speech and language disorder: FOXP2 is involved in the development of areas of the brain devoted to speech and language. Any mutation in FOXP2 causes developmental disorders in speech and language even in the absence of any other nervous system impairment. Individuals who are affected with this type of disorder have normal intelligence but face difficulty with speech and language.

Limitations
  • FOX family genes are involved in a number of critical processes in the body though their action is often complex and not well understood. Furthermore, these genes are often only active at key points in development or in certain biological contexts, which makes their study difficult, especially in humans. Though similar genes have been identified and studied in animals, how they relate or function in human beings is not always clear. A great deal of additional research remains to be done.

Safety




Future research
  • Earlier studies have indicated that FOX genes play a key role in the development of tissues and organs, in the aging process, as well as in the development of several types of diseases, including cancer. Recently, researchers have found that FOX genes play an important role in the development of lymphocytes. A lymphocyte is a type of white blood cell that helps fight against diseases and infections. Hence mutations in FOX genes may result in an impaired immune system, leading to the occurrence of several diseases.
  • Scientists have also found that FOXN1 is involved in the development and differentiation of the central nervous system. Any alteration in the FOXN1 genes may result in the development of nervous system disorders such as neural tube defect, a birth defect caused by the abnormal development of the neural tube (the structure which eventually develops into the spinal cord and brain).
  • Characterization of the FOX gene family and its various members may help in the development of new diagnostics methods, therapeutics (treatment options), prognostics (prediction of disease course), and methods for preventing diseases caused by mutations in FOX genes.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
  1. Amorosi S, D'Armiento M, Calcagno G, et al. FOXN1 homozygous mutation associated with anencephaly and severe neural tube defect in human athymic Nude/SCID fetus. Clin Genet. 2008 Apr;73(4):380-4.
  2. Demuth JP, De Bie T, Stajich JE, et al. The evolution of mammalian gene families. PLoS ONE. 2006 Dec 20;1:e85.
  3. Genetics Home Reference.
  4. Lai CS, Fisher SE, Hurst JA, et al. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001 Oct 4;413(6855):519-23.
  5. Katoh M, Katoh M. Human FOX gene family (Review). Int J Oncol. 2004 Nov;25(5):1495-500.
  6. National Cancer Institute.
  7. Natural Standard: The Authority on Integrative Medicine.
  8. Tang SY, Jiao Y, Li LQ. Significance of Forkhead Box m1b (Foxm1b) Gene in Cell Proliferation and Carcinogenesis. Ai Zheng. 2008 Aug;27(8):894-6.
  9. Vandenbark AA, Culbertson NE, Bartholomew RM, et al. Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis. Immunology. 2008 Jan;123(1):66-78.
  10. Wang X, Quail E, Hung NJ, et al. Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11468-73.

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