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.

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.

HADHB Gene

The official name of HADHB gene is hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme. The HADHB gene provides instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells. It is found in the mitochondrimitochondrial trifunctional proteina of several tissues, particularly the heart, liver, muscles, and the part of the eye that detects light and color (the retina).Mitochondrial trifunctional protein is required to break down (metabolize) a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils, and they are also stored in the body's fat tissues. Mitochondrial trifunctional protein is essential for converting long-chain fatty acids to the major source of energy used by the heart and muscles. During periods without food (fasting), this energy source is also important for the liver and other tissues.

Function:

As the name suggests, mitochondrial trifunctional protein performs three functions. It has three enzyme activities that are essential for fatty acid oxidation, which is the multistep process that metabolizes fats and converts them to energy. The beta subunit performs one of the enzyme activities, known as long-chain 3-keto-acyl-coenzyme A thiolase. The alpha subunit carries out the other two enzyme activities.

Location:

HADHA gene is present in human chromosome 2 and its coded from region 26321120 to 26366837 base pairs with 20 exons, the cytogenetic location 2p23.

Disease

Mutations in this gene causes mitochondrial trifunctional protein deficiency.

In mitochondrial trifunctional protein deficiency Researchers have identified at least 20 HADHB gene mutations that reduce all three enzyme activities of mitochondrial trifunctional protein. Most mutations change one of the building blocks (amino acids) used to make the protein's beta subunit. A change in amino acids probably alters the subunit's structure, which disrupts all three activities of the enzyme complex. Some mutations produce abnormally small, unstable beta subunits, which leads to a decreased amount of mitochondrial trifunctional protein. With a loss of mitochondrial trifunctional protein activity, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to the characteristic features of this disorder, such as lethargy and low blood sugar. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and muscles, causing more serious complications.

HADHA Gene

The official name of HADHA gene is hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), alpha subunit. The HADHA gene provides instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells. It is found in the mitochondria of several tissues, particularly the heart, liver, muscles, and the part of the eye that detects light and color (the retina).

Function:

Mitochondrial trifunctional protein is required to break down (metabolize) a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils, and they are also stored in the body's fat tissues. Mitochondrial trifunctional protein is essential for converting long-chain fatty acids to the major source of energy used by the heart and muscles. During periods without food (fasting), this energy source is also important for the liver and other tissues.Mitochondrial trifunctional protein is made of eight subunits. Four subunits called alpha are produced by the HADHA gene, and four subunits called beta are produced by the HADHB gene. As the name suggests, mitochondrial trifunctional protein performs three functions. It has three enzyme activities that are essential for fatty acid oxidation, which is the multistep process that metabolizes fats and converts them to energy. The alpha subunit performs two of the enzyme activities, known as long-chain 3-hydroxyacyl-coenzyme A dehydrogenase and long-chain 2-enoyl-coenzyme A hydratase. The beta subunit carries out the third enzyme activity.

Location:

HADHA gene is present in human chromosome 2 and its coded from region 26267008 to 26321098 base pairs with 20 exons, the cytogenetic location 2p23.

Disease

Mutations in this gene causes long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency(LCAD defiency) and Mitochondrial trifunctional protein deficiency

In LCAD defiency Researchers have identified several HADHA gene mutations that decrease the long-chain 3-hydroxyacyl-coenzyme A dehydrogenase enzyme activity of the mitochondrial trifunctional protein. (The protein's other enzyme activities remain normal or near normal.) Many of the HADHA mutations change one of the building blocks (amino acids) used to make the protein's alpha subunit. The most common mutation replaces the amino acid glutamic acid with the amino acid glutamine at position 474 in the alpha subunit. This mutation is written as Glu474Gln or E474Q. The Glu474Gln mutation and other amino acid replacements probably alter the structure of the alpha subunit, preventing it from functioning normally. Other types of HADHA mutations produce an abnormally small, unstable alpha subunit, which is unable to function. With a shortage (deficiency) of functional alpha subunits, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to the characteristic features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, such as lack of energy (lethargy) and low blood sugar. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and retina, causing more serious complications.

In mitochondrial trifunctional protein deficiency Researchers have identified several HADHA gene mutations that reduce all three enzyme activities of the mitochondrial trifunctional protein. Some mutations produce abnormally small, unstable alpha subunits, which leads to a decreased level of mitochondrial trifunctional protein. Other mutations replace one amino acid with another amino acid in the alpha subunit, which probably alters the subunit's structure and disrupts all three functions of the enzyme complex. With a loss of mitochondrial trifunctional protein activity, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to the characteristic features of this disorder, such as lethargy and low blood sugar. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and muscles, causing more serious complications.

COL5A2 Gene

The official name of COL5A2 gene is collagen, type V, alpha 2. The COL5A2 gene provides instructions for making a component of collagen. Collagens form a family of proteins that strengthen and support many tissues in the body, including skin, ligaments, bones, tendons, muscles, and the space between cells and tissues called the extracellular matrix.

Function:

The COL5A2 gene produces a component of type V collagen, called the pro-alpha2(V) chain. One pro-alpha2(V) chain combines with two pro-alpha1(V) chains (produced by the COL5A1 gene) to form type V procollagen. These triple-stranded, rope-like procollagen molecules must be processed by enzymes outside the cell. Once these molecules are processed, they arrange themselves into long, thin fibrils that cross-link to one another in the spaces around cells. The cross-links result in the formation of very strong, mature type V collagen fibers. Type V collagen also plays a role in assembling other types of collagen into fibrils within many connective tissues.

Location:

COL5A2 gene is present in human chromosome 2 and its coded from region 189604886 to 189752850 base pairs with 54 exons, the cytogenetic location 2q14-q32.

Disease

Mutations in this gene causes Ehlers-Danlos syndrome,Mutations in the COL5A2 gene have been identified in a small number of patients with classic Ehlers-Danlos syndrome. These mutations change the structure and function of the pro-alpha2(V) chain. As a result, type V collagen fibrils in the skin that are assembled with the altered protein are large and irregular. Researchers believe that these changes in collagen structure cause the signs and symptoms of classic Ehlers-Danlos syndrome.

AGXT gene

The official name of AGXT gene is alanine-glyoxylate aminotransferase.The AGXT gene provides instructions for making a liver enzyme called alanine-glyoxylate aminotransferase gene is expressed only in the liver and the encoded protein is localized mostly in the peroxisomes.This protein is important for several cellular activities such as ridding the cell of toxic substances and helping to break down certain fats. Peroxisomes contain several enzymes that are imported from the internal fluid of the cell (cytosol). Enzymes that are transferred into peroxisomes have a special arrangement of building blocks (amino acids) at one end of the enzyme that serves as a shipping address. In the peroxisome, alanine-glyoxylate aminotransferase converts a compound called glyoxylate to the amino acid glycine, which is later used for making enzymes and other proteins.

Peroxisome Proliferator-Activated Receptors


Location:

AGXT gene is present in human chromosome 2 and ts coded from region241456835 to 241467210 with 11 exons, the cytogenetic location 2q36-q37.

Disease

Mutation in the AGXT Gene causes type 1 primary hyperoxaluria. In some type 1 primary hyperoxaluria cases, alanine-glyoxylate aminotransferase enzyme activity is partially or entirely absent because of a mutation. As a result of this enzyme shortage, glyoxylate accumulates and is converted to a compound called oxalate instead of glycine. Oxalate, in turn, combines with calcium to form calcium oxalate, which the body cannot readily eliminate. Deposits of calcium oxalate can lead to kidney stones, kidney damage or failure, and injury to other organs, which are characteristic features of primary hyperoxaluria.

In other people with type 1 primary hyperoxaluria, the alanine-glyoxylate aminotransferase enzyme is misplaced within the cell. Misplacement occurs when certain mutations combine with a natural variation (polymorphism) in the gene. In most cases, a mutation replaces the amino acid glycine with the amino acid arginine at position 170 in the enzyme (written as Gly170Arg or G170R). This mutation occurs with a polymorphism that replaces the amino acid proline with the amino acid leucine at position 11 (written as Pro11Leu or P11L). The combined effect of the mutation and the polymorphism alters the structure of alanine-glyoxylate aminotransferase and changes the cellular shipping address of the enzyme. Instead of locating in peroxisomes, the enzyme is misdelivered to mitochondria, the energy-producing centers of cells. Even though the enzyme retains some of its activity, it cannot make contact with glyoxylate, which is located in peroxisomes. As a result, glyoxylate accumulates, leading to the signs and symptoms of primary hyperoxaluria.

ABCG8 Gene

The official name of ABCG8 is ATP-binding cassette, sub-family G (WHITE), member 8 (sterolin 2).The ABCG8 gene provides instructions for making a Sterolin-2 protein.Sterolin-1 and –2 are two ‘half’ adenosine triphosphate binding (ATP) cassette (ABC) transporters which found to be indispensable for the regulation of sterol absorption and excretion.The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. The protein encoded by this gene functions to exclude non-cholesterol sterol entry at the intestinal level, promote excretion of cholesterol and sterols into bile, and to facilitate transport of sterols back into the intestinal lumen. It is expressed in a tissue-specific manner in the liver, intestine, and gallbladder. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG5.

Location:

ABCG5 gene is present in human chromosome 2 and ts coded from region 43919607 to 43959109 complement with 13 exons, the cytogenetic location 2p21.

Disease

Mutations in both alleles of either ABCG5 or ABCG8 in the human results in sitosterolemia. Sitosterolemia (also known as phytosterolemia) is a rare autosomal recessively inherited lipid metabolic disorder characterized by the presence of tendon xanthomas, premature coronary artery disease and atherosclerotic disease, hemolytic episodes, arthralgias and arthritis. The hallmark of sitosterolemia is diagnostically elevated levels of plant sterols in the plasma.

ABCA12 Gene

The official name of ABCA12 is ATP-binding cassette, sub-family A (ABC1), member 12.The USH2A gene provides instructions for making a protein called ATP-binding cassette (ABC) transporter. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This encoded protein is a member of the ABC1 subfamily, which is the only major ABC subfamily found exclusively in multicellular eukaryotes. Alternative splicing of this gene results in multiple transcript variants.

Location:

USH2A gene is present in human chromosome 2 and ts coded from region 215504511 to 215711396 complement with 53 exons, the cytogenetic location 2q34.

Disease

Mutations iin the ABCA12 gene have been identified in people with harlequin ichthyosis. Harlequin ichthyosis is a severe genetic disorder that mainly affects the skin. Infants with this condition are born with very hard, thick skin covering most of their bodies. The skin forms large, diamond-shaped plates that are separated by deep cracks (fissures). These skin abnormalities affect the shape of the eyelids, nose, mouth, and ears, and limit movement of the arms and legs. Restricted movement of the chest can lead to breathing difficulties and respiratory failure.ABCA12 gene mutations probably lead to an absence of ABCA12 protein or the production of an extremely small version of the protein that cannot transport lipids properly. A lack of lipid transport causes numerous problems with the development of the epidermis before and after birth. Specifically, it prevents the skin from forming an effective barrier against fluid loss (dehydration) and infections, and leads to the formation of hard, thick scales characteristic of harlequin ichthyosis.

The below Video is in very disturbing.I added this video only to show how cruel this disorder is.