Exostosin glycosyltransferase-2 is a protein that in humans is encoded by the EXT2 gene. [5] [6] [7]
This gene encodes one of two glycosyltransferases involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type II form of Hereditary Multiple Exostoses (HME). [7]
The EXT2 gene is located on chromosome 11 in the human genome, its location is on the p arm of this chromosome. [8] The p arm of a chromosome is the shorter arm of a chromosome. [9]
Included in the EXT family are EXT2, EXT1, EXTL1, EXTL2, and EXTL3. The proteins formed by these genes work together to form and extend heparan sulfate chains. Heparan sulfate chains are proteoglycans present in the extracellular matrix of most tissue types. There is a lot about its function that is not entirely understood, however it is known that they have an important role for bone and cartilage formation. [10] Cartilage is located at the growth plates of long bones and is placed in a specific pattern before it is later ossified into bone when it grows further away from the growth plate. New cartilage in a growing bone is placed through signaling proteins which bind to the heparan sulfate chains. [11] EXT2 (protein) has also been shown to interact with TRAP1, a heat shock protein. [12] Heat shock proteins will bind to specific proteins to help them keep their shape when the cell is stressed. [13] TRAP1 has been found to bind to a region (in the c-terminal end) of EXT1 and EXT2 proteins to help it keep its desired shape and function. [14]
This gene was found to be present in many species other than humans such as mice, chickens, dogs, cows and many more. Other orthologs have been found including Drosophila melanogaster and Caenorhabditis elegans. [15]
Mutations that change the amino acid sequence of the exostosin glycosyltransferase-2 protein can lead to it becoming unfunctional. When this protein is unfunctional it causes the heparan sulfate chains to become shorter. The chains are still formed and extended by the other proteins encoded by the EXT family genes, although not to the same extent. This increases the likelihood that a cartilage cell will be placed incorrectly, as heparan sulfate is a bone and cartilage tumor suppressor. Since bone has a very specific structure, misplacing a cartilage cell in early growth is comparable to misplacement of a brick early on in construction of a wall. Misplacement in cartilage will result in cartilage tumor or tumors at the growth plates of long bones. This condition is known as hereditary multiple exostoses (HME) or hereditary multiple osteochondromas (HMO). [16] HME can also be the result of a mutation to the EXT1 gene or other EXT family genes. [17] EXT1 mutations tend to be more severe with more exostoses and are the cause of 56-78% of human HME cases, except for in China where mutations of the EXT2 gene are more common. HME effects 1 in 50,000 people and is more commonly seen in males in a 1.5:1 ratio. [18]
EXT2 gene mutations are dominant autosomal (not sex-linked) and is lethal in the homozygous form. This means that if the mutated gene is inherited from both parents giving the offspring two copies of the mutated gene (the homozygous form of the mutant gene) this will result in early embryonic death in the gastrula stage of development. Reasons for why this happens is that heparan sulfate has more roles than just bone formation, it also plays a role in embryonic development. Heparan sulfate can bind signaling molecules used in development such as transforming growth factor β, Fgf proteins and Wnt proteins. The only individuals with this mutation exist in the heterozygous form, this means that they have one EXT2 gene that is normal and one that is mutated. For the inheritance of this gene mutation, for a mutated parent and a not mutated parent there is a 50% chance that the offspring will also have an EXT2 mutation. For two parents with the EXT2 mutation, of their living offspring 2 out of 3 will have the mutation. [19]
Hereditary multiple osteochondromas (HMO), also known as hereditary multiple exostoses, is a disorder characterized by the development of multiple benign osteocartilaginous masses (exostoses) in relation to the ends of long bones of the lower limbs such as the femurs and tibias and of the upper limbs such as the humeri and forearm bones. They are also known as osteochondromas. Additional sites of occurrence include on flat bones such as the pelvic bone and scapula. The distribution and number of these exostoses show a wide diversity among affected individuals. Exostoses usually present during childhood. The vast majority of affected individuals become clinically manifest by the time they reach adolescence. A small percentage of affected individuals are at risk for development of sarcomas as a result of malignant transformation. The incidence of hereditary multiple exostoses is around 1 in 50,000 individuals. Hereditary multiple osteochondromas is the preferred term used by the World Health Organization.
Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.
Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.
A benign tumor is a mass of cells (tumor) that does not invade neighboring tissue or metastasize. Compared to malignant (cancerous) tumors, benign tumors generally have a slower growth rate. Benign tumors have relatively well differentiated cells. They are often surrounded by an outer surface or stay contained within the epithelium. Common examples of benign tumors include moles and uterine fibroids.
Osteochondromas are the most common benign tumors of the bones. The tumors take the form of cartilage-capped bony projections or outgrowth on the surface of bones exostoses. It is characterized as a type of overgrowth that can occur in any bone where cartilage forms bone. Tumors most commonly affect long bones about the knee and in the forearm. Additionally, flat bones such as the pelvis and scapula may be affected. Hereditary multiple exostoses usually present during childhood. Yet, the vast majority of affected individuals become clinically manifest by the time they reach adolescence. Osteochondromas occur in 3% of the general population and represent 35% of all benign tumors and 8% of all bone tumors. The majority of these tumors are solitary non-hereditary lesions and approximately 15% of osteochondromas occur as hereditary multiple exostoses preferably known as hereditary multiple osteochondromas (HMOs). Osteochondromas do not result from injury and the exact cause remains unknown. Recent research has indicated that multiple osteochondromas is an autosomal dominant inherited disease. Germ line mutations in EXT1 and EXT2 genes located on chromosomes 8 and 11 have been associated with the cause of the disease. The treatment choice for osteochondroma is surgical removal of solitary lesion or partial excision of the outgrowth, when symptoms cause motion limitations or nerve and blood vessel impingements. In hereditary multiple exostoses the indications of surgery are based upon multiple factors that are taken collectively, namely: patient's age, tumor location and number, accompanying symptomatology, esthetic concerns, family history and underlying gene mutation. A variety of surgical procedures have been employed to remedy hereditary multiple exostoses such as osteochondroma excision, bone lengthening, corrective osteotomy and hemiepiphysiodesis. Sometimes a combination of the previous procedures is used. The indicators of surgical success in regard to disease and patient characteristics are greatly disputable. Because most studies of hereditary multiple exostoses are retrospective and of limited sample size with missing data, the best evidence for each of the currently practiced surgical procedures is lacking.
Metachondromatosis is an autosomal dominant, incompletely penetrant genetic disease affecting the growth of bones, leading to exostoses primarily in the hands and feet as well as enchondromas of long bone metaphyses and iliac crests. This syndrome affects mainly tubular bones, though it can also involve the vertebrae, small joints, and flat bones. The disease is thought to affect exon 4 of the PTPN11 gene. Metachondromatosis is believed to be caused by an 11 base pair deletion resulting in a frameshift and nonsense mutation. The disease was discovered and named in 1971 by Pierre Maroteaux, a French physician, when he observed two families with skeletal radiologic features with exostoses and Ollier disease. The observation of one family with five affected people led to the identification of the disease as autosomal dominant. There have been less than 40 cases of the disease reported to date.
Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 146 million base pairs and represents between 4.5 and 5.0% of the total DNA in cells.
Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins.
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. It is in this form that HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.
Syndecan 1 is a protein which in humans is encoded by the SDC1 gene. The protein is a transmembrane heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors and chemokines, with binding largely via heparan sulfate chains. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein.
The sulfate transporter is a solute carrier family protein that in humans is encoded by the SLC26A2 gene. SLC26A2 is also called the diastrophic dysplasia sulfate transporter (DTDST), and was first described by Hästbacka et al. in 1994. A defect in sulfate activation described by Superti-Furga in achondrogenesis type 1B was subsequently also found to be caused by genetic variants in the sulfate transporter gene. This sulfate (SO42−) transporter also accepts chloride, hydroxyl ions (OH−), and oxalate as substrates. SLC26A2 is expressed at high levels in developing and mature cartilage, as well as being expressed in lung, placenta, colon, kidney, pancreas and testis.
In enzymology, a N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase is an enzyme that catalyzes the chemical reaction
Exostosin-1 is a protein that in humans is encoded by the EXT1 gene.
Heat shock protein 75 kDa, mitochondrial is a protein that in humans is encoded by the TRAP1 gene.
Exostosin-like 3 is a protein that in humans is encoded by the EXTL3 gene.
Exostosin-like 1 is a protein that in humans is encoded by the EXTL1 gene.
Exostosin-like 2 is a protein that in humans is encoded by the EXTL2 gene. EXTL2 Glycosyltransferase is required for the biosynthesis of heparan-sulfate and responsible for the alternating addition of beta-1-4-linked glucuronic acid (GlcA) and alpha-1-4-linked N-acetylglucosamine (GlcNAc) units to nascent heparan sulfate chains.
Trevor disease, also known as dysplasia epiphysealis hemimelica and Trevor's disease, is a congenital bone developmental disorder. There is 1 case per million population. The condition is three times more common in males than in females.
Glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase is an enzyme with systematic name UDP-N-acetyl-D-glucosamine:beta-D-glucuronosyl-(1->3)-beta-D-galactosyl-(1->3)-beta-D-galactosyl-(1->4)-beta-D-xylosyl-proteoglycan 4IV-alpha-N-acetyl-D-glucosaminyltransferase. This enzyme catalyses the following chemical reaction
Glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase is an enzyme with systematic name UDP-N-acetyl-D-glucosamine:beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase. This enzyme catalyses the following chemical reaction
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