BRCA1

BRCA1 (breast cancer 1, early onset) is a human gene, some mutations of which are associated with a significant increase in the risk of breast cancer, as well as other cancers. BRCA1 belongs to a class of genes known as tumor suppressors, which maintains genomic integrity to prevent uncontrolled proliferation. The multifactorial BRCA1 protein product is involved in DNA damage repair, ubiquitination, transcriptional regulation as well as other functions.

Gene location

The BRCA1 gene is located on the long (q) arm of chromosome 17 at band 21, from base pair 38,449,843 to base pair 38,530,933

BRCA1 2 pathway prevents leukemias and lymphomas


Function and mechanism
DNA damage repair

The BRCA1 protein is directly involved in the repair of damaged DNA. In the nucleus of many types of normal cells, the BRCA1 protein is thought to interact with RAD51 during repair of DNA double-strand breaks, though the details and significance of this interaction is the subject of debate. These breaks can be caused by natural radiation or other exposures, but also occur when chromosomes exchange genetic material (homologous recombination, e.g. "crossing over" during meiosis). The BRCA2 protein, which has a function similar to that of BRCA1, also interacts with the RAD51 protein. By influencing DNA damage repair, these three proteins play a role in maintaining the stability of the human genome.

BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the MRN complex as well as the nuclease activity of Mre11 alone. This may explain a role for BRCA1 to promote higher fidelity DNA repair by NHEJ. BRCA1 also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.

Transcription

BRCA1 was shown to co-purify with the human RNA Polymerase II holoenzyme in HeLa extracts, implying it is a component of the holoenzyme. Later research, however, contradicted this assumption, instead showing that the predominant complex including BRCA1 in HeLa cells is a 2 megadalton complex containing SWI/SNF. SWI/SNF is a chromatin remodeling complex. Artificial tethering of BRCA1 to chromatin was shown to decondense heterochromatin, though the SWI/SNF interacting domain was not necessary for this role.BRCA1 interacts with the NELF-B (COBRA1) subunit of the NELF complex.

Mutations and cancer risk

Certain variations of the BRCA1 gene lead to an increased risk for breast cancer. Researchers have identified more than 600 mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer.

These mutations can be changes in one or a small number of DNA base pairs (the building blocks of DNA). Those mutations can be identified with PCR and DNA sequencing.

In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene. Classical methods for mutations detection(sequencing) are unable to reveal those mutations. Other methods are proposed: Q-PCR, Multiplex Ligation-dependent Probe Amplification (MLPA), and Quantitative Multiplex PCR of Shorts Fluorescents Fragments (QMPSF). New methods have been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on comparative genomic hybridization (array-CGH).

A mutated BRCA1 gene usually makes a protein that does not function properly because it is abnormally short. Researchers believe that the defective BRCA1 protein is unable to help fix mutations that occur in other genes. These defects accumulate and may allow cells to grow and divide uncontrollably to form a tumor.

In addition to breast cancer, mutations in the BRCA1 gene also increase the risk on ovarian, fallopian tube and prostate cancers. Moreover, precancerous lesions (dysplasia) within the Fallopian tube have been linked to BRCA1 gene mutations.

SLC40A1 gene

The official name of SLC40A1 gene is “solute carrier family 40 (iron-regulated transporter), member 1".SLC40A1 gene belongs to a family of genes called SLC. SLC40A1 gene provides instructions for making a protein called ferroportin 1. This protein plays an essential role in the regulation of iron levels in the body. Iron from the diet is absorbed through the walls of the small intestine. Ferroportin 1 then transports iron from the small intestine into the bloodstream. In the bloodstream, the iron binds to another transport protein called transferrin that carries it to the tissues and organs of the body. Ferroportin 1 also transports iron out of specialized immune system cells (called reticuloendothelial cells) that are found in the liver, spleen, and bone marrow. The iron balance in the body is regulated by the amount of iron stored and released from these cells.



Location:

SLC40A1 is present in human chromosome 2 and its coded from region190,133,560 to 190,153,857 Complement base pairs with 8 exons, the cytogenetic location 2q32

Disease

Mutations in SLC40A1 gene causes hemochromatosis Approximately 15 mutations SLC40A1 have been identified which causes type 4 hemochromatosis, Almost all of these mutations change a single protein building block (amino acid) in ferroportin 1. Abnormal versions of ferroportin 1 do not permit the normal transport and release of iron from intestinal or reticuloendothelial cells. As a result, the regulation of iron levels in the body is impaired and iron overload results. One mutated copy of this gene in each cell is sufficient to cause type 4 hemochromatosis, sometimes referred to as ferroportin disease.

PAX 8 Gene

The official name of PAX8 gene is “paired box 8". The PAX8 gene belongs to a family of genes that plays a critical role in the formation of tissues and organs during embryonic development. The PAX gene family is also important for maintaining the normal function of certain cells after birth. To carry out these roles, the PAX genes provide instructions for making proteins that attach to specific areas of DNA. By attaching to critical DNA regions, these proteins help control the activity of particular genes (gene expression). On the basis of this action, PAX proteins are called transcription factors.

During embryonic development, the PAX8 protein is thought to activate genes involved in the formation of the kidney and the thyroid gland. The thyroid gland is a butterfly-shaped tissue in the lower neck. It releases hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). Following birth, the PAX8 protein regulates several genes involved in the production of thyroid hormones.

PAX8 protein


 

Location:

PAX8 Gene is present in human chromosome 2 and its coded from region113,691,409 to 113,752,967 Complement base pairs with 9 exons, the cytogenetic location 2q12-q14.

Disease

Mutations in PAX8 gene causes congenital hypothyroidism.Several PAX8 mutations have been identified, but the effect of these mutations on health is variable. Some mutations cause congenital hypothyroidism, while others mildly reduce thyroid hormone levels or have no detectable effect. In some cases, identical mutations in members of the same family have varied effects.

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Most mutations change one of the building blocks (amino acids) used to make the PAX8 protein. Other mutations disrupt protein production, resulting in an abnormally small version of the PAX8 protein. Nearly all PAX8 mutations prevent the PAX8 protein from effectively binding to DNA. One mutation alters interactions between the PAX8 protein and other transcription factors. As a result, the PAX8 protein cannot perform its role in regulating the activity of certain genes.

The thyroid gland is unusually small in people with PAX8 mutations. This finding suggests that PAX8 mutations disrupt the normal growth or survival of thyroid cells during embryonic development. As a result, the thyroid gland is reduced in size and may be unable to produce the normal amount of thyroid hormones.

PAX3 gene

The official name of PAX3 gene is “paired box 3". The PAX3 gene belongs to a family of genes that plays a critical role in the formation of tissues and organs during embryonic development. The PAX gene family is also important for maintaining the normal function of certain cells after birth. To carry out these roles, the PAX genes provide instructions for making proteins that attach to specific areas of DNA. By attaching to critical DNA regions, these proteins help control the activity of particular genes. On the basis of this action, PAX proteins are called transcription factors.

During embryonic development, the PAX3 gene is active in cells called neural crest cells. These cells migrate from the developing spinal cord to specific regions in the embryo. The protein made by the PAX3 gene directs the activity of other genes (such as MITF) that signal neural crest cells to form specialized tissues or cell types such as limb muscles, bones in the face and skull (craniofacial bones), some nerve tissue, and pigment-producing cells called melanocytes. Melanocytes produce the pigment melanin, which contributes to hair, eye, and skin color. Melanocytes are also found in certain regions of the brain and inner ear.

Location:

PAX3 Gene is present in human chromosome 2 and its coded from region 222,772,850 to 222,871,943 Complement base pairs with 9  exons, the cytogenetic location 2q35-q37.

PAX3 Protein

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Disease

Mutations in PAX3  gene causes Waardenburg syndrome   Several PAX3 mutations have been identified in people with Waardenburg syndrome, types I and III. Some of these mutations change one of the chemical building blocks (amino acids) used to make the PAX3 protein. Other mutations lead to an abnormally small version of the PAX3 protein. Researchers believe that all PAX3 mutations have the same effect; they destroy the ability of the PAX3 protein to bind to DNA and regulate the activity of other genes. As a result, melanocytes do not develop in certain areas of the skin, hair, eyes, and inner ear, leading to hearing loss and the patchy loss of pigmentation that are characteristic features of Waardenburg syndrome. Additionally, loss of PAX3 protein function disrupts development of craniofacial bones and certain muscles, producing the limb and facial features that are unique to Waardenburg syndrome, types I and III.

    Alterations in the activity of the PAX3 gene are associated with some cases of cancer of muscle tissue (alveolar rhabdomyosarcoma) that occur mainly in adolescents and young adults. Gene activity is altered when the PAX3 gene on chromosome 2 is fused with the FOXO1A gene (also called FKHR) on chromosome 13. This fusion event occurs when segments of chromosomes 2 and 13 are rearranged in certain cells that develop into muscle tissue. The fused PAX3-FOXO1A gene may enhance changes that can lead to cancer, such as uncontrolled cell division and cell growth.

# Arnold K., Bordoli L., Kopp J., and Schwede T. (2006). The SWISS-MODEL Workspace: A web-based environment for protein structure homology modelling. Bioinformatics, 22,195-201.
# Schwede T, Kopp J, Guex N, and Peitsch MC (2003) SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Research 31: 3381-3385.

# Guex, N. and Peitsch, M. C. (1997) SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modelling. Electrophoresis 18: 2714-2723.

OTOF Gene

The official name of OTOF gene is “otoferlin". The OTOF gene provides instructions for making a protein called otoferlin. This protein is present in the brain and the cochlea, which is a snail-shaped structure in the inner ear that helps process sound. Although the exact function of otoferlin is uncertain, it appears to be essential for normal hearing. Researchers believe that otoferlin may play a role in releasing chemical signals (neurotransmitters) from nerve cells that are involved in hearing. This process is dependent on the concentration of calcium within the cell. The otoferlin protein has several regions called C2 domains that bind to calcium and use it to interact with other molecules.

Location:

OTOF Gene is present in human chromosome 2 and its coded from region 26,533,574 to 26,635,069 base pairs with 47 exons, the cytogenetic location 2p23.1.

Disease

Mutations in OTOF gene causes  nonsyndromic deafness     At least 16 mutations in the OTOF gene have been identified in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB9. People with these mutations have a type of hearing loss called auditory neuropathy, which occurs when sound is not transmitted properly from the inner ear to the brain.

    Some mutations in the OTOF gene result in the production of an abnormally small, nonfunctional version of otoferlin or prevent cells from making any of this protein. Other genetic changes probably alter the 3-dimensional structure of otoferlin, which impairs its ability to bind to calcium.

    A particular OTOF mutation is a common cause of nonsyndromic deafness in the Spanish population. This mutation replaces one amino acid building block, glutamine, with a signal that stops protein production prematurely at position 829 in the otoferlin protein (written as Gln829Ter or Q829X). The Q829X mutation causes an abnormally short version of otoferlin to be made, which disrupts the protein's function and leads to hearing loss.

NR4A2 gene

The official name of NR4A2 gene is “nuclear receptor subfamily 4, group A, member 2". The MSH6 gene provides instructions for making a member of steroid-thyroid hormone-retinoid receptor superfamily. that may plays a role as a Trascription factor. This protein found in the brain and the adrenal gland (the hormone-producing gland located on top of each kidney). In the brain, the NR4A2 protein plays a key role in prompting certain nerve cells to specialize (differentiate) and produce a chemical messenger called dopamine. Dopamine transmits messages that help the brain control physical movement and emotional behavior.

NR4A2 prot direct interactions

image coursey: Oliver Brun
Location:

NR4A2 gene is present in human chromosome 2 and its coded from region 156,889,194 to 156,897,445 base pairs with 8 exons, the cytogenetic location 2q22-q23.

Disease

Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson disease, schizophernia, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis. Alternatively spliced transcript variants have been described, but their biological validity has not been determined.

MSH6 Gene

The official name of MSH2 gene is “mutS homolog 6 (E. coli)". The MSH6 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein fixes mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH6 protein joins with another protein, the MSH2 protein, to form an active protein complex. This active protein complex identifies places on the DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then takes over to help with the actual repair. The MSH6 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

Location:

MSH2 gene is present in human chromosome 2 and its coded from region 47,863,789 to 47,887,595 base pairs with 16 exons, the cytogenetic location 2p16.

Disease

Mutations in the MSH6 gene have been reported in about 10 percent of families with Lynch syndrome that have an identified gene mutation. All of these mutations cause the production of an abnormally short, nonfunctional MSH6 protein or a partially active version of the protein. When the MSH6 protein is absent or ineffective, the number of mistakes that are left unrepaired during cell division increases substantially. If the cells continue to divide, errors accumulate in DNA; the cells become unable to function properly and may form a tumor in the colon or another part of the body. People with mutations in the MSH6 gene also have an increased risk of developing cancers of the ovary, stomach, small intestine, liver, gallbladder duct, upper urinary tract, brain, and skin.

MSH2 Gene

The official name of MSH2 gene is “mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)". TThe MSH2 gene provides instructions for making a protein that plays an essential role in DNA repair. This protein fixes mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH2 protein joins with one of two other proteins, the MSH6 protein or the MSH3 protein, to form an active protein complex. This active protein complex identifies places on the DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then takes over to help with the actual repair. The MSH2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

Location:

MSH2 gene is present in human chromosome 2 and its coded from region 47,483,766 to 47,563,863 base pairs with 16 exons, the cytogenetic location 2p22-p21.

Disease

Mutations in this gene causes increases the risk of Lynch syndrome, About 40 percent of all cases of Lynch syndrome with an identified gene mutation are associated with mutations in the MSH2 gene. Several hundred MSH2 mutations that predispose people to colorectal cancer and other HNPCC-associated cancers have been found. These mutations may cause the production of an abnormally short or inactivated MSH2 protein that cannot perform its normal function. When the MSH2 protein is absent or ineffective, the number of mistakes that are left unrepaired during cell division increases substantially. If the cells continue to divide, errors accumulate in DNA; the cells become unable to function properly and may form a tumor in the colon or another part of the body. People with mutations in the MSH2 gene have an increased risk of developing several other types of cancer, including cancers of the endometrium (lining of the uterus), ovary, stomach, small intestine, liver, gallbladder duct, upper urinary tract, brain, and skin. Some mutations in the MSH2 gene increase the likelihood of several uncommon skin tumors occurring in addition to colorectal cancer, a combination called Muir-Torre syndrome. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in skin glands (sebaceous glands) that produce an oily substance called sebum. Multiple, rapidly growing skin tumors called keratoacanthomas may also occur, usually on sun-exposed areas.