BMPR2 gene

The official name of BMPR2 gene is bone morphogenetic protein receptor, type II (serine/threonine kinase).The BMPR2 gene provides instructions for making a protein called bone morphogenetic protein receptor. Bone morphogenetic protein receptor, type II spans the cell membrane, so that one end of the protein is on the outer surface of the cell and the other end remains inside the cell. This arrangement allows the protein to receive and transmit signals that help the cell respond to its environment by growing and dividing (cell proliferation) or by undergoing controlled cell death (apoptosis). This balance of cell proliferation and cell death regulates the number of cells in tissues.

Function:

On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP-7, BMP-2 and, less efficiently, BMP-4. Binding is weak but enhanced by the presence of type I receptors for BMPs

Location:

BMPR gene is present in human chromosome 2 and its coded from region 202,949,916 to 203,140,719 with 13 exons, the cytogenetic location 2q33-q34

Disease

Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease.Researchers have identified more than 140 BMPR2 mutations that cause pulmonary arterial hypertension. About half of these mutations disrupt the assembly of bone morphogenetic protein receptor, type II, reducing the amount of this protein in cells. Other mutations prevent bone morphogenetic protein receptor, type II from reaching the cell surface, or alter its structure so it cannot receive or transmit signals.

It remains unclear how BMPR2 mutations cause pulmonary arterial hypertension. Researchers suggest that a mutation in this gene promotes cell proliferation or prevents cell death, resulting in an overgrowth of cells in the smallest arteries throughout the lungs. As a result, these arteries narrow in diameter, which increases the resistance to blood flow through the lungs. To overcome the increased resistance, pressure increases in the pulmonary artery and in the heart chamber that pumps blood into the pulmonary artery (the right ventricle). Signs and symptoms of pulmonary arterial hypertension occur when increased pressure cannot fully overcome the elevated resistance and blood flow to the body is insufficient.

ALS2 Gene

The official name of ALS2 gene is amyotrophic lateral sclerosis 2 (juvenile)..The ALS2 gene provides instructions for making a protein called alsin. Alsin is produced in a wide range of tissues, with highest amounts in the brain. It is particularly abundant in motor neurons, the specialized nerve cells in the brain and spinal cord that control the movement of muscles.

Alsin's function in cells is unclear. It may play a role in regulating cell membrane organization and the movement of molecules inside cells. Research findings also suggest that alsin may play a role in the development of axons and dendrites, which are specialized outgrowths from nerve cells that are essential for the transmission of nerve impulses.

Location:

ALS2 gene is present in human chromosome 2 and ts coded from region 202,273,521 to 202,353,982 with 34 exons, the cytogenetic location 2q33.2

Disease

Mutation in the ALS2 Gene causes Amyotrophic lateral Sclerosis(ALS),infantile-onset ascending hereditary spastic paralysis ,juvenile primary lateral sclerosis.In all three disease mutations delete a single DNA building block (nucleotide), which alters the instructions for producing alsin. As a result, alsin is unstable and decays rapidly.

ALMS1 Gene

The official name of ALMS1 gene is Alstrom syndrome 1.The ALMS1 gene provides instructions for making a protein whose function is unknown. Researchers believe that the protein may play a role in hearing, vision, regulation of body weight, and functions of the heart, kidney, lungs, and liver. It may also affect how the pancreas regulates insulin, a hormone that helps control blood sugar levels.

The ALMS1 protein is present in most of the body's tissues, usually at low levels. Within cells, this protein is located in structures called centrosomes. Centrosomes play a role in cell division and the assembly of microtubules, which are proteins that transport materials in cells and help the cell maintain its shape. The ALMS1 protein is also found at the base of cilia, which are finger-like projections that stick out from the surface of cells. Almost all cells have cilia at some stage of their life cycle. Cilia are involved in cell movement and many different chemical signaling pathways. Based on its location within cells, researchers suggest that the ALMS1 protein might be involved in the organization of microtubules, the transport of various materials, and the normal function of cilia.

Location:

ALMS1 gene is present in human chromosome 2 and ts coded from region 73,466,393 to 73,690,553 with 23 exons, the cytogenetic location 2p13

Disease

Mutation in the ALMS1 Gene causes Alström syndrome. Most of these mutations lead to the production of an abnormally small version of the ALMS1 protein that does not function properly. Researchers propose that a lack of normal ALMS1 function in the brain could lead to overeating. A loss of this protein in the pancreas may cause insulin resistance, a condition in which the body cannot use insulin properly. The combined effects of overeating and insulin resistance impair the body's ability to handle excess sugar, leading to diabetes and obesity (two common features of Alström syndrome). It is unclear how ALMS1 mutations cause the other signs and symptoms of Alström syndrome. Researchers suspect that this condition is associated with malfunctioning cilia in many of the body's tissues and organs.

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.

ABCG5 Gene

The official name of ABCG5 is ATP-binding cassette, sub-family G (WHITE), member 5.The ABCG5 gene provides instructions for making a sterolin1 protein OF ABC group proteins. 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.

Location:

ABCG5 gene is present in human chromosome 2 and ts coded from region 43893115 to 43919462 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.

USH2A gene

The official name of USH2A gene is Usher syndrome 2A (autosomal recessive, mild)..The USH2A gene provides instructions for making anan enzyme called usherin. Usherin is an important component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Usherin is found in the inner ear and the part of the eye that detects light and color (the retina). Although the function of usherin has not been well established, studies suggest that this protein is part of a larger protein complex that plays an important role in inner ear and retinal development. In these locations, the protein complex may also be involved in the function of synapses, which are junctions between nerve cells where cell-to-cell communication occurs.

Location:

USH2A gene is present in human chromosome 1 and ts coded from region 213,862,858 to 214,663,360 complement with 71 exons, the cytogenetic location 1q41.

Disease

Mutations in USH2A gene causes a form of  Usher syndrome type IIA,Usher syndrome is a condition characterized by hearing loss or deafness and progressive vision loss. The loss of vision is caused by an eye disease called retinitis pigmentosa (RP), which affects the layer of light-sensitive tissue at the back of the eye (the retina). Vision loss occurs as the light-sensing cells of the retina gradually deteriorate.Mutations change single protein building blocks (amino acids) in the usherin protein. In some cases, these mutations lead to the production of an abnormally short version of the protein or prevent the cell from making any functional usherin. Other mutations insert or delete small amounts of DNA in the USH2A gene, which probably impairs the normal function of usherin. Researchers have not determined how a missing or altered usherin protein leads to the signs and symptoms of Usher syndrome.The most common mutation in the USH2A gene is found in about 25 percent of people with Usher syndrome type IIA, particularly those from Europe, the United States, South Africa, and China. This mutation deletes a specific DNA building block, a guanine (G) nucleotide, at position 2299 in the USH2A gene (written as 2299delG). Individuals with this change, or with similar mutations in the USH2A gene, develop moderate to severe hearing loss and retinitis pigmentosa, a disorder that results in loss of vision.

UROD Gene

The official name of UROD gene is uroporphyrinogen decarboxylase.The UROD gene provides instructions for making anan enzyme called uroporphyrinogen decarboxylase. Uroporphyrinogen III decarboxylase (UroD) is a homodimeric enzyme which catalyzes the fifth step in heme biosynthesis: the elimination of carboxyl groups from the four acetate side chains of uroporphyrinogen III to yield coproporphyrinogen III.Three additional enzymes modify this product before it becomes heme. The heme molecule is then incorporated into hemoglobin and packaged into red blood cells, or it is used in the liver for the production of certain liver enzymes.

Location:

UROD gene is present in human chromosome 1 and ts coded from region 45250417 to 45253928 with 10 exons, the cytogenetic location 1p34.

Disease

Mutations in UROD gene causes a form of porphyria called porphyria cutanea tarda and hepatoerythropoietic porphyria,In porphyria cutanea tarda the mutations occur in one of the two copies of the UROD gene in each cell, which usually reduces the activity of uroporphyrinogen decarboxylase by 50 percent throughout the body.As a result, byproducts of heme production called porphyrins build up in the body, particularly in the liver. This buildup, in combination with nongenetic factors (such as alcohol, smoking, certain hormones, excess iron, and viral infections), causes this type of porphyria.

In hepatoerythropoietic porphyria Most of the mutations are unique in this type of porphyria and have not been found in porphyria cutanea tarda. Mutations that cause hepatoerythropoietic porphyria occur in both copies of the UROD gene in each cell, which reduces the activity of uroporphyrinogen decarboxylase to less than 10 percent of normal. Extremely low levels of this enzyme prevent sufficient amounts of heme from being produced. As a result, byproducts of heme production called porphyrins build up in the body, causing this type of porphyria.

TSHB Gene

The official name of TSHB gene is thyroid stimulating hormone, beta.The TSHB gene provides instructions for making a protein subunit of a hormone called thyroid stimulating hormone (TSH). Thyroid stimulating hormone consists of two subunits called alpha and beta. The TSHB gene provides instructions for making the beta (B) subunit of thyroid stimulating hormone. The alpha and beta subunits are bound together to produce the active form of the hormone. A particular segment of the beta subunit, known as the buckle or seatbelt, wraps around the alpha subunit to form the functional hormone.

Thyroid stimulating hormone is made in the pituitary gland, a gland at the base of the brain. This hormone plays an important role in the growth and function of the thyroid gland, a butterfly-shaped tissue in the lower neck. It also stimulates the production of thyroid hormones, which play a critical role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). The pituitary gland monitors levels of thyroid hormones. When thyroid hormone levels are too low, the pituitary gland releases thyroid stimulating hormone into the bloodstream. Thyroid stimulating hormone, in turn, signals increased thyroid gland growth and production of thyroid hormones.

Location:

TSHB gene is present in human chromosome 1 and ts coded from region 115373938 to 115378464, the cytogenetic location 1p13

Disease

Researchers have identified several TSHB mutations that alter the size or shape of the thyroid stimulating hormone beta subunit. Many of these mutations affect the beta subunit's seatbelt region, which holds the alpha subunit in place and stabilizes the hormone's structure. Some mutations severely shorten the beta subunit, eliminating the seatbelt region partially or entirely. Other mutations change the chemical building blocks (amino acids) used to make the beta subunit. As a result, the seatbelt region cannot buckle around the alpha subunit. TSHB mutations prevent the production of functional thyroid stimulating hormone or its release (secretion) from the pituitary gland. As a result, thyroid hormone production is not stimulated, leading to low hormone levels that are characteristic of congenital hypothyroidism. Additionally, the thyroid gland is reduced in size (hypoplastic) because its growth is not stimulated.

SDHB Gene

The official name of SDHB gene is succinate dehydrogenase complex, subunit B, iron sulfur (Ip),The SDHB  gene provides instructions for making a protein called succinate dehydrogenase(SDH). The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). The SDHB subunit is connected to the SDHA subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an iron-sulfur protein with three iron-sulfur clusters. It weighs 30 kDa.The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain.

SDHB acts as an intermediate in the basic SDH enzyme action:

   1. SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2.
   2. Electrons from the FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S].
   3. Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits.This function is part of the Respiratory chain.

Sporadic and familial mutations in this gene result in paragangliomas (glomus tumors)and pheochromocytoma, and support a link between mitochondrial dysfunction and tumorigenesis.

Mutations causing disease have been seen in exons 1 through 7, but not 8. As with the SDHC and SDHD genes, SDHB is a tumor suppressor gene. Note the SDHA gene is not a tumor suppressor gene.

Tumor formation generally follows the Knudson "two hit" hypothesis. The first copy of the gene is mutated in all cells, however the second copy functions normally. When the second copy mutates in a certain cell due to a random event, Loss of Heterozygosity (LOH) occurs and the SDHB protein is no longer produced. Tumor formation then becomes possible.

Given the fundamental nature of the SDH protein in all cellular function, it is not currently understood why only paraganglionic cells are affected. However, the sensitivity of these cells to oxygen levels may play a role.

PSEN2 gene

The official name of PSEN2 gene is presenilin 2 (Alzheimer disease 4),The PSEN2 gene provides instructions for making a protein called presenilin 2. Presenilin 2 helps process certain proteins that are important for transmitting biochemical signals from the cell membrane into the nucleus of the cell. In the nucleus, these signals turn on (activate) particular genes that are important for cell growth and maturation. Presenilin 2 is also involved in processing amyloid precursor protein, which is found in the brain and other tissues. Research suggests that presenilin 2 works as part of an enzyme complex that cuts amyloid precursor protein into smaller segments (peptides). One of these peptides is called soluble amyloid precursor protein (sAPP) and another is called amyloid beta peptide. Recent evidence suggests that sAPP has growth-promoting properties and may play a role in the formation of nerve cells in both embryonic and adult brain tissue. Other functions of sAPP and amyloid beta peptide are under investigation.

Location:
PSEN gene is present in human chromosome 1 and ts coded from region 225124896 to 225150427, the cytogenetic location 1q31-q42

Disorder:
Mutations in this gene causes Alzheimer's disease 4

Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1 or PSEN2) or the amyloid precursor protein (APP).Researcher have found approxiametly 11 mutaions in PSEN gene have been shown to cause type 4 Alzheimer disease.Two of the most common PSEN2 mutations that cause type 4 Alzheimer disease change one of the building blocks (amino acids) used to make presenilin 2. One mutation replaces the amino acid asparagine with the amino acid isoleucine at position 141 (written as Asn141Ile or N141I). The other mutation changes the amino acid methionine to the amino acid valine at position 239 (written as Met239Val or M239V). These mutations appear to affect the processing of amyloid precursor protein.These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor such that, they either directly regulate gamma-secretase activity, or themselves act are protease enzymes. Two alternatively spliced transcript variants encoding different isoforms of PSEN2 have been identified.