HAS2 gene

HAS2 (Hyaluronan Synthase 2) is a protein-coding gene located on chromosome 8q24.13. The HAS2 gene is a member of a highly conserved vertebrate gene family encoding hyaluronan synthases. The amino acid sequence of HAS2 synthetase shows significant homology to glycosaminoglycan synthetase (DG42) from Xenopus laevis and to human and mouse hyaluronan synthase 1.

Hyaluronic acid (also hyaluran/HA) is an unbranched polysaccharide with a high molecular weight that is synthesized by a wide range of organisms, from bacteria to mammals. The substance is a component of the extracellular matrix. It consists of alternating glucuronic acid and N-acetylglucosamine residues linked by beta-1-3 and beta-1-4 glycosidic bonds. Hyaluronic acid (HA) is synthesized by a membrane-bound synthase at the inner surface of the plasma membrane. Hyaluronic acid synthase 2 catalyzes the attachment of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer (Karousou E et al. 2010). From the cell, the polysaccharide chains are discharged into the extracellular space through pore-like structures.

Hyaluronic acid performs a variety of functions, including maintaining skin turgor, and providing a matrix important for cell migration. HA is an essential component of synovial fluid. HA is actively produced during wound healing and tissue repair. In this process, the poysaccharide aggregates to form a scaffold that is important for the ingrowth of blood vessels and fibroblasts. Furthermore, the interaction of HA with the leukocyte receptor CD44 is important for the tissue-specific settlement of leukocytes. Overexpression of HA receptors has been associated with tumor metastasis. Alterations in serum concentrations of HA have been associated with inflammatory and degenerative joint diseases such as rheumatoid arthritis, as well as cutaneous mucinosis.

In Shar-Pei fibroblasts (Shar-Pei is a rare dog breed - Chinese wrinkled dog with a diffuse mucinosis of the skin) a higher mRNA expression of the isoform HAS2 was detected, so that a mutation in the HAS2 gene can be assumed. Fibroblasts of Shar-Pei dogs are morphologically altered. Scanning electron microscopy showed a large number of cellular protrusions with associated spherical deposits.

Diseases associated with HAS2 include:

• Mucopolysaccharidosis, type IX

and

• colorectal cancer.

Associated metabolic pathways include glycosaminoglycan metabolism and metabolism. Gene Ontology (GO) annotations related to this gene include hyaluronan synthase activity.

1. Docampo MJ et al (2011) Increased HAS2-driven hyaluronic acid synthesis in shar-pei dogs with hereditary cutaneous hyaluronosis (mucinosis). Vet Dermatol 22:535-345.
2. Kasai K et al (2020) Phosphorylation of Thr328 in hyaluronan synthase 2 is essential for hyaluronan synthesis. Biochem Biophys Res Commun 533:732-738.
3. Karousou E et al. (2010) The activity of hyaluronan synthase 2 is regulated by dimerization and ubiquitination. J Biol Chem 285: 23647-23654.
4. Vigetti D et al. (2011) Hyaluronan synthesis is inhibited by adenosine monophosphate-activated protein kinase through the regulation of HAS2 activity in human aortic smooth muscle cells. J Biol Chem 286:7917-7924.
5. Zanna G et al (2008) Cutaneous mucinosis in shar-pei dogs is due to hyaluronic acid deposition and is associated with high levels of hyaluronic acid in serum. Vet Dermatol 19:314-418.