Exostosin glycosyltransferase-2 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''EXT2''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. This gene encodes one of two glycosyltransferases involved in the chain elongation step of

heparan sulfate Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs in a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...

biosynthesis. Mutations in this gene cause the type II form of Hereditary Multiple Exostoses (HME).

Gene location

The EXT2 gene is located on chromosome 11 in the human genome, its location is on the p arm of this chromosome. The p arm of a chromosome is the shorter arm of a chromosome.

Interactions

Included in the EXT family are EXT2,

EXT1 Exostosin-1 is a protein that in humans is encoded by the ''EXT1'' gene. This gene encodes one of the two endoplasmic reticulum-resident type II transmembrane glycosyltransferase – the other being EXT2 – which are involved in the chain elon ...

, EXTL1, EXTL2, and EXTL3. The proteins formed by these genes work together to form and extend heparan sulfate chains. Heparan sulfate chains are

proteoglycans Proteoglycans are proteins that are heavily glycosylation, glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalent bond, covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a ...

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 Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...

formation. 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. EXT2 (protein) has also been shown to interact with TRAP1, a heat shock protein. Heat shock proteins will bind to specific proteins to help them keep their shape when the cell is stressed. 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.

Species Distribution

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 ''Drosophila melanogaster'' is a species of fly (an insect of the Order (biology), order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly" ...

and

Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a Hybrid word, blend of the Greek ''caeno-'' (recent), ''r ...

Mutations

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). HME can also be the result of a mutation to the EXT1 gene or other EXT family genes. 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.

Heredity of the EXT2 Gene

EXT2 gene mutations are dominant

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...

(not sex-linked) and is lethal in the

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

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 Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of Cell (biology), cells), or in mammals, the blastocyst, is reorganized into a two-layered or three-layered e ...

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 Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

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.

References

External links

Multiple Hereditary Exostoses Research Foundation
{{Glycosaminoglycan metabolism enzymes