Human Genetic Disorders Caused by Mutations in Genes Encoding Biosynthetic Enzymes for Sulfated Glycosaminoglycans

Abstract

A number of genetic disorders are caused by mutations in the genes encoding glycosyltransferases and sulfotransferases, enzymes responsible for the synthesis of sulfated glycosaminoglycan (GAG) side chains of proteoglycans, including chondroitin sulfate, dermatan sulfate, and heparan sulfate. The phenotypes of these genetic disorders reflect disturbances in crucial biological functions of GAGs in human. Recent studies have revealed that mutations in genes encoding chondroitin sulfate and dermatan sulfate biosynthetic enzymes cause various disorders of connective tissues. This minireview focuses on growing glycobiological studies of recently described genetic diseases caused by disturbances in biosynthetic enzymes for sulfated GAGs.

Sulfation patterns of exogenous chondroitin sulfate affect chondrogenic differentiation of ATDC5 cells

“…These functions are closely associated with the sulfation patterns of the CS moieties. Moreover, mutations in the genes of sulfotransferases, active sulfate synthetase or nucleotide-sugar transporters, which are indispensable for the synthesis of CS, cause chondrodysplasia in mice and humans [9][10][11][12][13][14]. These findings confirm that the sulfation of CS plays a critical role in chondrogenic differentiation.…”

Identification of Chondroitin Sulfate Linkage Region Glycopeptides Reveals Prohormones as a Novel Class of Proteoglycans

“…This part of the biosynthesis is the same for CS and heparan sulfate (HS). However, for CS the biosynthesis continues with the addition of an N-acetylgalactosamine (GalNAc␤3), whereas HS biosynthesis continues with the addition of an N-acetylglucosamine (GlcNAc␣4) (6). The CS-chains are thereafter elongated through the addition of repeating units of GlcA and GalNAc and are further modified by the addition of specifically positioned sulfate groups (7).…”

Effects of sesamin on the biosynthesis of chondroitin sulfate proteoglycans in human articular chondrocytes in primary culture

“…To investigate effects of sesamin on the expression of the genes encoding aggrecan (ACAN) and CS biosynthetic enzymes including XYLT1, XYLT2, CHSY1, and CHPF as well as the content of GAGs, two different HAC culture systems, monolayer and pellet cultures, were utilized in this study. It is notable that full production of CS-GAG is essential for healthy cartilage development as genetic defects of certain glycosyltransferases and sulfotransferases involved in the biosynthesis of CS-GAGs cause developmental delay, short stature, generalized osteopenia, chondrodysplasia, craniofacial dysmorphism, and OA [22,27]. …”

“…Therefore, here we studied using cultured HAC (human articular chondrocytes) systems, the effects of sesamin on the gene expression of the core protein of the major CS-PG, aggrecan and on the glycosyltransferases required for the attachment of CS side chains on the aggrecan core protein. Aggrecan core protein is encoded by the ACAN gene, which is highly expressed in cartilagenous tissues [19][20][21][22]. XYLT1 and XYLT2 encode xylosyltransferase I (XylT1) and xylosyltransferase II (XylT2), respectively, which catalyze the initial enzymatic reaction in the assembly of GAGs onto core proteins.…”