Table 2.
GAG biosynthesis enzymes implicated in defects observed in patient samples.
| Gene deficiency consequences evidenced in patient samples | |||||
|---|---|---|---|---|---|
| Protein name | Function | GAG | PG | Other glycosylation defects | |
| Linker | |||||
| XYLT1 | Xylosyltransferase 1 (MIM: 608124) | Transfer of a Xyl residue from UDP-Xyl to specific serine residues of PG core protein Götting et al., 2007 | Reduced total GAG synthesis after incubation with methylumbelliferyl-β-D-xylopyranoside in patient fibroblasts Bui et al., 2014 | Reduced glycosylation of decorin in patient fibroblast supernatants Schreml et al., 2014 | N.D |
| XYLT2 | Xylosyltransferase 2 (MIM: 608125) | Transfer of a Xyl residue from UDP-Xyl to specific serine residues of PG core protein Götting et al., 2007 | Reduced HS staining in patient fibroblasts and reduced CS and HS chains synthesis in patient fibroblasts Munns et al., 2015 | N.D. | N.D. |
| FAM20B | Glycosaminoglycan xylosylkinase (MIM: 611063) | Phosphorylates initiator xylose residue Koike et al., 2009 | N.D. | N.D. | N.D. |
| B4GALT7 | Galactosyltransferase I (MIM: 604327) | Transfer of first Gal residue to Ser-O-Xyl of tetrasaccharide linkage region Okajima et al., 1999 | Reduced epimerization of GAG chain in patient fibroblasts Seidler et al., 2006 | Defective biosynthesis of mature decorin and biglycan in patient fibroblasts Quentin et al., 1990; Seidler et al., 2006 Reduced level of bikunin bearing CS chain on Western blot in patient serum Bruneel et al., 2018; Haouari et al., 2020 |
N.D. |
| B3GALT6 | β-1,3-Galactosyltransferase 6 (MIM: 615291) | Transfer of second Gal residue to Ser-O-Xyl-Gal of tetrasaccharide linkage region Bai et al., 2001 | Reduced HS chains and increased CS and DS chains in patient lymphoblastoid cells Nakajima et al., 2013 Reduced total GAG synthesis in patient fibroblasts Malfait et al., 2013 Disorganized HS GAG ECM in patient fibroblasts Ritelli et al., 2015 |
Impaired glycanation of decorin in patient fibroblasts Malfait et al., 2013 Reduced level of bikunin bearing CS chain on Western blot in patient serum Bruneel et al., 2018; Haouari et al., 2020 Reduced perlecan immunostaining in patient fibroblasts Ritelli et al., 2015 |
N.D. |
| B3GAT3 | β-1,3-Glucuronyltransferase 3 (MIM: 606374) | Transfer of a GlcUA residue to Ser-O-Xyl-Gal-Gal of tetrasaccharide linkage region Pedersen et al., 2000 | Reduced CS, DS, and HS chains synthesis in patient fibroblasts Baasanjav et al., 2011 | Increased level of DS-free decorin in patient fibroblasts Baasanjav et al., 2011 Reduced level of bikunin bearing CS chain on Western blot in patient serum Bruneel et al., 2018; Haouari et al., 2020 |
N.D. |
| CS/DS chain elongation | |||||
| CSGALNACT1 | Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (MIM: 616615) | Transfer of GalNAc residue onto linker region for initiation of CD/DS synthesis Sato et al., 2003 | Reduced number of CS/DS chains in patient fibroblasts Mizumoto et al., 2020 | Normal PG synthesis Vodopiutz et al., 2017 | N.D. |
| CSGALNACT2 | Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (MIM: 616616) | CS/DS chain elongation Sato et al., 2003 | N.D. | N.D. | N.D. |
| CHSY1 | Chondroitin sulfate synthase 1 (MIM: 608183) | CS/DS chain elongation Uyama et al., 2002 | Decreased CS immunostaining in patient skin Tian et al., 2010 | Reduced molecular weight of bikunin bearing CS chain on Western blot in patient serum Bruneel et al., 2018 | N.D. |
| CHPF | Chondroitin polymerizing factor (MIM: 610405) | CS/DS chain elongation Kitagawa et al., 2001 | N.D. | N.D. | N.D. |
| CHPF2 | Chondroitin polymerizing factor 2 (MIM: 608037) | CS/DS chain elongation Izumikawa et al., 2008 | N.D. | N.D. | N.D. |
| DSE | Dermatan sulfate epimerase (MIM: 605942) | Epimerization of GlcUA of CS chain into IdoUA converting CS to DS Malmström and Aberg, 1982 | Decreased DS disaccharides in patient fibroblasts Müller et al., 2013 | Glycanation of decorin is impaired in patient fibroblasts Müller et al., 2013 | |
| DSEL | Dermatan sulfate epimerase-like (MIM: 611125) | Epimerisation of GlcUA of CS chain into IdoUA converting CS to DS Pacheco et al., 2009 | N.D. | N.D. | N.D. |
| HS chain elongation | |||||
| EXTL1 | Exostosin-like glycosyltransferase 1 (MIM: 601738) | Transfer of GlcNAc residues to tetrasaccharide linkage region for initiation of HS synthesis Kim et al., 2001 | N.D. | N.D. | N.D. |
| EXTL2 | Exostosin-like glycosyltransferase 2 (MIM: 602411) | Transfer of a GlcNAc residue to a phosphorylated tetrasaccharide linkage region to stop chain elongation Nadanaka et al., 2013b | N.D. | N.D. | N.D. |
| EXTL3 | Exostosin-like glycosyltransferase 3 (MIM: 605744) | Transfer of a GlcNAc residue to tetrasaccharide linkage region for initiation of HS synthesis Kim et al., 2001 | Lower HS concentration in patient fibroblasts, increased CS and DS concentrations in patient serum and urine Oud et al., 2017 Abnormal HS sulfation pattern in patient fibroblasts Volpi et al., 2017 |
N.D. | N.D. |
| EXT1/EXT2 | Exostosin glycosyltransferase 1 (MIM: 608177)/Exostosin glycosyltransferase 2 (MIM: 608210) | HS polymerization McCormick et al., 2000 | Reduced HS/CS ratio in patient serum Anower-E-Khuda et al., 2013 | N.D. | N.D. |
| Sulfation | |||||
| SLC26A2 | DTD sulfate transporter (MIM: 606718) | Transports sulfate ions across cell membrane Hästbacka et al., 1994 | Undersulfated CS in patient fibroblasts and cartilage Rossi et al., 1998 | N.D. | N.D. |
| PAPSS1 | 3'-phosphoadenosine 5'-phosphosulfate synthase (MIM: 603262) |
Synthetizes universal sulfate donor (PAPS) Xu et al., 2000 | N.D. | N.D. | N.D. |
| PAPSS2 | 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (MIM: 603005) |
Synthetizes universal sulfate donor (PAPS) Xu et al., 2000 | Undersulfation of CS in patient urine Toledo et al., 1978 | N.D. | N.D. |
| SLC35B2 (PAPST1) | Solute carrier family 35 (3'-phosphoadenosine 5'-phosphosulfate transporter), member B2 (MIM: 610788) | Transports PAPS from cytosol to Golgi Kamiyama et al., 2003 | N.D. | N.D. | N.D. |
| SLC35B2 (PAPST2) | Solute carrier family 35 (3'-phosphoadenosine 5'-phosphosulfate transporter), member B2 (MIM: 610845) | Transports PAPS from cytosol to Golgi Kamiyama et al., 2006 | N.D. | N.D. | N.D. |
| CHST3 | Carbohydrate sulfotransferase 3 (MIM: 603799) | Transfers sulfate from PAPS to C6 of GalNAc residues of CS Tsutsumi et al., 1998 | Reduction of 6-O-sulfated disaccharide in patient fibroblasts and urine Thiele et al., 2004. Increase of 4-O-sulfated disaccharide in patient fibroblasts Hermanns et al., 2008 | N.D. | N.D. |
| CHST11 | Carbohydrate sulfotransferase 11 (MIM: 610128) | Transfers sulfate from PAPS to GalNAc residues of DS Hiraoka et al., 2000 | N.D. | N.D. | N.D. |
| CHST14 | Carbohydrate sulfotransferase 14 (MIM: 608429) | Transfers sulfate from PAPS to C4 of GalNAc residues of CS Evers et al., 2001 | Reduced DS biosynthesis and increased CS concentration in patient fibroblasts Dündar et al., 2009; Miyake et al., 2010 DS not detected in patient urines Mizumoto et al., 2017 |
Decorin depleted of DS chains, replaced by CS chains in patient fibroblasts Miyake et al., 2010 | N.D. |
| IMPAD1 | Inositol monophosphate domain-containing protein 1 (MIM: 614010) | Hydrolyses by-product of sulfotransferase reactions, PAP, in AMP and phosphate Frederick et al., 2008 | N.D. | N.D. | N.D. |
| Transporter or other | |||||
| SLC35D1 | Solute carrier family 35 (UDP-glucuronic acid/UDP-N-acetylgalactosamine dual transporter), member D1 (MIM: 610804) | Transports UDP-GlcUA/UDP-GalNAc from cytosol to Golgi Muraoka et al., 2001 | N.D. | N.D. | N.D. |
| SLC35A3 | Solute carrier family 35 (UDP-N-acetyl glucosamine transporter), member 3 (MIM: 605632) | Transports UDP-GlcNAc from cytosol to Golgi Maszczak-Seneczko et al., 2013 | N.D. | Reduced molecular weight of bikunin bearing CS chain on Western blot in patient serum Haouari et al., 2020 | Reduced N-glycan branching in patient cells and plasma Edvardson et al., 2013 |
| SLC10A7 | Solute carrier family 10 (sodium:bile acid cotransporter family), member 7 (MIM: 611459) | Negative regulator of intracellular calcium homeostasis Karakus et al., 2020 | Significant reduction of HS proportion linked to increased CS proportion in patient fibroblasts Dubail et al., 2018 | N.D. | Defective N glycosylation in patient serum Ashikov et al., 2018; Dubail et al., 2018 |
| CANT1 | Calcium-activated nucleotidase 1 (MIM: 613165) | Hydrolyses UDP to UMP and phosphate in Golgi Smith et al., 2002 | Reduced GAG synthesis after stimulation by β-D-xyloside in patient fibroblasts Nizon et al., 2012b | N.D. | N.D. |
| TGDS | TDP-glucose 4,6-dehydratase (MIM: 616146) | cTDP-D-glucose 4,6-dehydrogenase homologous to a UDP-glucuronate decarboxylase 1 that catalyzes synthesis of UDP-xylose from UDP-glucuronate Ehmke et al., 2014 | N.D. | N.D. | N.D. |
| TMEM165 | Transmembrane protein 165 (MIM: 614726) | Putative role of Mn2+ transporter Dulary et al., 2017 | N.D. | Reduced molecular weight of bikunin bearing CS chain on Western blot in patient serum Haouari et al., 2020 | Increased undersialylated and undergalactosylated glycans in patient serum Foulquier et al., 2012; Xia et al., 2013; Zeevaert et al., 2013 |