Abstract
Congenital disorders of glycosylation (CDGs) are a group of diseases characterized by an abnormal glycosylation of proteins or lipids. It is estimated that more than half of all proteins in our body are glycosylated [1]. Defined as all the sugar chains (glycans) that an organism makes, the glycome is estimated to be 102–104 times larger than the proteome [2]. Given this complexity, it is not surprising that about 2% of our genes encode for proteins that are currently known to participate in glycosylation reactions []. CDGs are classified according to the deficient glycosylated substrates, which can include proteins, lipids, or multiple substrates.
Introduction
Congenital disorders of glycosylation (CDGs) are a group of diseases characterized by an abnormal glycosylation of proteins or lipids. It is estimated that more than half of all proteins in our body are glycosylated [1]. Defined as all the sugar chains (glycans) that an organism makes, the glycome is estimated to be 102–104 times larger than the proteome [2]. Given this complexity, it is not surprising that about 2% of our genes encode for proteins that are currently known to participate in glycosylation reactions [3]. CDGs are classified according to the deficient glycosylated substrates, which can include proteins, lipids, or multiple substrates. The classification of disorders of hypoglycosylation is divided into: (1) defects in protein N-linked glycosylation (glycans attached to the amino [N-] group of asparagine residues), (2) defects in protein O-linked glycosylation (sugars are attached to the hydroxyl [O-] groups of serine or threonine), (3) defects in glycosphingolipid and in glycosylphosphatidylinositol-anchor glycosylation, and (4) defects in multiple glycosylation pathways. No human disorders have been discovered yet in association with abnormal C-linked glycosylation [4].
The initial steps of N-glycosylation take place on the cytosolic side of the endoplasmic reticulum (ER) membrane, whereupon initial activation sugars are attached in a stepwise manner to dolichol pyrophosphate (Dol-PP) to form a lipid-linked oligosaccharide (LLO). First, two N-acetylglucosamines (GlcNAc) are attached to Dol-PP, followed by the addition of five mannose (Man) residues to form a Man5GlcNAc2 intermediate which is then translocated or “flipped” to the luminal side of the ER membrane. Up to this step, the sugars were donated by an activated nucleotide-sugar (UDP-GlcNAc and GDP-Man), with the attached nucleotide providing the necessary energy for the transfer of the sugar to the LLO. Once on the luminal side of the ER, the sugar donors are dolichylphosphoglucose (Dol-P-Glc) and dolichylphosphomannose (Dol-P-Man); subsequent sugars are attached to the LLO to finally form Glc3Man9GlcNAc2. This oligosaccharide is removed from its dolichol stem and transferred to a nascent protein by the action of an oligosaccharyltransferase (OST), a complex composed of eight subunits. Once the oligosaccharide chain has been transferred to the protein, further processing takes place, first by trimming the distal glucose by the action of a glycosidase in the ER. Then, the oligosaccharide is transported to the Golgi apparatus, where further removal of glucose and mannose residues and addition of other sugars take place by the action of several enzymes, e.g. mannosidases, fucosyltransferases, and sialyltransferases. Different types of CDGs have been found in affected individuals who have defective enzymes in individual steps of this complex pathway including dolichol synthesis and utilization, enzymes that transfer single sugars to the growing chain, interconvert activated monosaccharides, transfer the oligosaccharide from dolichol to protein, transport activated sugars across membranes, transfer glycosyl transferases between different vesicular compartments, and other integral steps.
O-glycosylation differs from N-glycosylation in that it occurs exclusively post-translationally, and only in the Golgi apparatus. There are many different types of O-glycosylation according to which type of sugar is attached to serine or threonine. For example, defects of O-mannosylation lead to an underglycosylation of alpha-dystroglycan, a protein necessary for the attachment of the subsarcolemmal cytoskeleton of the skeletal muscle cell to the extracellular matrix. When this protein is not glycosylated adequately, its anchoring function is lost, leading to various types of congenital muscular dystrophies. Defects in O-xylosylation lead to defective anchoring of glycosaminoglycans (GAGs) to proteins. Since many proteoglycans are important components of the skeleton and connective tissue, disorders of GAG synthesis usually lead to skeletal dysplasias or connective-tissue disorders.
Incorrectly glycosylated lipids can also lead to significant clinical issues, including intellectual disability, seizures, and spastic paraplegias. The biosynthesis of glycosylphosphatidylinositol (GPI) anchors, required for the attachment of over 150 human proteins to the plasma membrane [5], requires the concerted activity of more than 20 enzymes, the deficiency of most of which have been associated with human disease.
Many of the genetic defects of glycosylation involve multiple pathways. Examples are combined N- and O-glycosylation defects, like abnormal dolichol-phosphate mannose (DPM) synthesis, affecting ER-related mannosylation, O-mannosylation, and GPI-anchor biosynthesis, and disorders associated with the function of the components of the conserved oligomeric Golgi (COG) protein complex. Finally, NGLY1 deficiency represents a unique congenital disorder of deglycosylation with phenotypic similarities to CDGs, given that intracellular free oligosaccharides are not efficiently recycled into the glycosylation pathway.
In this chapter, we summarize the current knowledge on CDGs, with particular emphasis on the movement disorder accompanying some of them.
History, Nomenclature, and Classification of CDGs
CDGs were originally described in 1980 [6] in twin sisters, who were subsequently found to have hyposialylation of serum and cerebrospinal fluid (CSF) transferrin [7]. Two more patients had been described by 1984 [8], and seven more in Sweden by 1989 [9]. The condition was briefly known as disialotransferrin developmental deficiency syndrome. Twenty-six patients were presented by Dr. Jaak Jaeken and Dr. Helena Stibler at the Fifth International Congress of Inborn Errors of Metabolism (ICIEM, Asilomar, June 1–5, 1990), where the condition came to be known as carbohydrate-deficient glycoprotein syndrome. New subtypes were subsequently identified based on clinical and sialotransferrin differences. A new variant was described in 1991 [10], and came to be known as carbohydrate-deficient glycoprotein syndrome type II [11], and soon afterwards further subtypes were identified, known as type III [12] and type IV [13].
The enzymes and genes responsible for the first known CDGs were identified in the 1990s. The enzyme deficiency associated with carbohydrate-deficient glycoprotein syndrome type II was identified in 1994 [14] and the gene, in 1996 [15], while the enzyme associated with the carbohydrate-deficient glycoprotein syndrome type I was identified in 1995 [16] and the gene, in 1997 [17], and the enzyme and gene deficiencies responsible for type IV were described in 1999 [18]. Once the enzyme deficiencies came to be known, a new classification system was proposed by the participants of the First International Workshop on Carbohydrate-Deficient Glycoprotein Syndromes in Leuven, Belgium, that took place in 1999. Carbohydrate-deficient glycoprotein syndromes then became known as congenital disorders of glycosylation [19, 20]. CDGs were named according to the type of transferrin isoelectric focusing (IEF) abnormality, followed by a letter of the alphabet in the order in which they were described. For example, a deficiency of phosphomannomutase was called CDG-Ia (corresponding to carbohydrate-deficient glycoprotein syndrome type I), while carbohydrate-deficient glycoprotein syndrome type II came to be known as CDG-IIa, and carbohydrate-deficient glycoprotein syndrome type IV was renamed CDG-Id.
This classification system, however, presented some problems. First, some subtypes of disorders of N-glycosylation were not associated with abnormalities in transferrin IEF, such as for example CDG-IIb. Second, transferrin IEF only assesses N-glycosylation, since transferrin lacks any O-glycosylation sites; thus, defects in O-glycosylation were not amenable to this classification. Third, several disorders came to be known that did not include abnormalities in protein glycosylation, but rather lipid glycosylation. Fourth, this classification provided no biological insight about the basic protein defect. Fifth, there are too few letters of the alphabet to name all newly discovered CDGs – this occurred when the disorder associated with mutations in NUS1 was designated CDG-Iaa. Thus, a new nomenclature system was proposed in 2008 [21, 22], to include the official gene symbol (not in italics) followed by “-CDG”. As an example, the new nomenclature for CDG-Ia would be PMM2-CDG.
Table 19.1 summarizes the gene name and locus, protein deficiency and function, and disease nomenclature and inheritance pattern of the 149 different CDGs known to date.
| Gene | Gene locus OMIM number | Function | Localization of defect | Disease | Inheritance | Initial molecular characterization (PMID) |
|---|---|---|---|---|---|---|
| N-linked glycosylation defects | ||||||
| Interconversion of monosaccharides | ||||||
| PMM2 | 601785 |
| Cytosol | PMM2-CDG (CDG-Ia) | AR | 9140401 |
| MPI | 154550 |
| Cytosol | MPI-CDG (CDG-Ib) | AR | 9525984 |
| N-glycan lipid-linked oligosaccharide assembly | ||||||
| DPAGT1 | 191350 | GlcNAc-1-P-transferase (transfers 1st GlcNAc) | ER (cytosolic side) | DPAGT1-CDG (CDG-Ij); CMS13 | AR | 12872255 |
| ALG13 | 300776 | UDP-GlcNAc-transferase (transfers 2nd GlcNAc) | ER (cytosolic side) | ALG13-CDG (CDG-Is) in males; EEIE36 in females | XL | 22492991 |
| ALG14 | 612866 | UDP-GlcNAc transferase (transfers 2nd GlcNAc) | ER (cytosolic side) | CMS15 | AR | 23404334 |
| ALG1 | 605907 | β1–4 Man-transferase (transfers 1st mannose) | ER (cytosolic side) | ALG1-CDG (CDG-Ik) | AR | 14709599, 14973778, 14973782 |
| ALG2 | 607905 | α1–3/6 Man-transferase (transfers 2nd and 3rd mannoses) | ER (cytosolic side) | ALG2-CDG (CDG-Ii); CMS14 | AR | 12684507 |
| ALG11 | 613666 | α1–2 Man-transferase (transfers 4th and 5th mannoses) | ER (cytosolic side) | ALG11-CDG (CDG-Ip) | AR | 20080937 |
| RFT1 | 611908 | Man5GlcNAc2-PP-Dol flippase | ER | RFT1-CDG (CDG-In) | AR | 18313027 |
| ALG3 | 608750 | α1–3 Man-transferase (transfers 6th mannose) | ER (luminal side) | ALG3-CDG (CDG-Id) | AR | 10581255 |
| ALG9 | 606941 | α1–2 Man-transferase (transfers 7th and 9th mannoses) | ER (luminal side) | ALG9-CDG (CDG-IL); Gillessen–Kaesbach–Nishimura syndrome | AR | 15148656 |
| ALG12 | 607144 | α1–6 Man-transferase (transfers 8th mannose) | ER (luminal side) | ALG12-CDG (CDG-Ig) | AR | 11983712 |
| ALG6 | 604566 | α1–3 Glc-transferase (transfers 1st glucose) | ER (luminal side) | ALG6-CDG (CDG-Ic) | AR | 10359825 |
| ALG8 | 608103 | α1–3 Glc-transferase (transfers 2nd glucose) | ER (luminal side) | ALG8-CDG (CDG-Ih); polycystic liver disease 3 | AR, AD | 12480927; 28375157 |
| Glycan transfer to nascent protein | ||||||
| TUSC3 | 601385 | OST subunit | ER | TUSC3-CDG (MRT7/MRT22) | AR | 18455129, 18452889 |
| DDOST | 614507 | OST subunit | ER | DDOST-CDG (CDG-Ir) | AR | 22305527 |
| STT3A | 601134 | OST subunit | ER | STT3A-CDG (CDG-Iw) | AR | 23842455 |
| STT3B | 608605 | OST subunit | ER | STT3B-CDG (CDG-Ix) | AR | 23842455 |
| MAGT1 | OST subunit | ER | MAGT1-CDG; XMEN | XL | 21796205 | |
| SSR4 | 300090 | Translocon-associated protein, delta subunit | ER | SSR4-CDG (CDG-Iy) | XL | 24218363 |
| SEC63 | 608648 | Translocon-associated protein | ER | Polycystic liver disease 2 | AD | 15133510 |
| N-glycan processing | ||||||
| MOGS | 601336 | α1–2 glucosidase I (removes Glc from Glc3Man9GlcNAc2) | ER | MOGS-CDG (CDG-IIb) | AR | 10788335 |
| GANAB | 104160 | α1–3 glucosidase II subunit alpha (removes last two Glc from Glc2Man9GlcNAc2) | ER | Polycystic kidney disease 3 | AD | 27259053 |
| PRKCSH | 177060 | α1–3 glucosidase II subunit beta (removes last two Glc from Glc2Man9GlcNAc2) | ER | Polycystic liver disease 1 | AD | 12529853, 12577059 |
| MAN1B1 | 604346 | α1–2 mannosidase I (removes Man from Man9GlcNAc2 ➔ Man8GlcNAc2 isomer B) | ER | MAN1B1-CDG (MRT15) | AR | 21763484 |
| MGAT2 | 602616 | β1–2 GlcNAc-transferase II (transfers GlcNAc to GlcNAcMan3GlcNAc2) | Medial-Golgi | MGAT2-CDG (CDG-IIa) | AR | 8808595 |
| B4GALT1 | 137060 | β1–4 Gal-transferase (transfers Gal to either arm of GlcNAc2Man3GlcNAc2) | Trans-Golgi | B4GALT1-CDG (CDG-IId) | AR | 11901181 |
| FUT8 | 602589 | α1–6 Fuc-transferase (adds core fucose) | Golgi | FUT8-CDG | AR | 29304374 |
| O-linked glycosylation defects | ||||||
| O-mannosylation | ||||||
| POMT1 | 607423 | Protein O-Man-transferase | ER | MDDGA1, MDDGB1, MDDGC1 | AR | 12369018 |
| POMT2 | 607439 | Protein O-Man-transferase | ER | MDDGA2, MDDGB2, MDDGC2 | AR | 15894594 |
| POMGNT1 | 606822 | β1–2 GlcNAc-transferase (transfers GlcNAc to Man in core M1) | Golgi | MDDGA3, MDDGB3, MDDGC3, RP76 | AR | 11709191 |
| POMGNT2 | 614828 | β1–4 GlcNAc-transferase (transfers GlcNAc to Man in core M3) | ER | MDDGA8 | AR | 22958903 |
| B3GALNT2 | 610194 | β1–3 GalNAc-transferase II (transfers GalNAc to GlcNAcMan in core M3) | ER | MDDGA11 | AR | 23453667 |
| POMK | 615247 | Phosphorylates 6-position of Man after addition of GlcNAc and GalNAc | ER | MDDGA12, MDDGC12 | AR | 23519211 |
| ISPD | 614631 | Synthesizes CDP-ribitol | Cytosol | MDDGA7, MDDGC7 | AR | 22522420, 22522421 |
| FKTN | 607440 | Adds ribitol-5-P to GalNAcGlcNAcMan6P | Golgi | MDDGA4, MDDGB4, MDDGC4 | AR | 9690476 |
| FKRP | 606596 | Adds ribitol-5-P to Rbo5PGalNAcGlcNAcMan6P | Golgi | MDDGA5, MDDGB5, MDDGC5 | AR | 11592034 |
| RXYLT1 | 605862 |
| Golgi | MDDGA10 | AR | 23217329 |
| B4GAT1 | 605581 | β-1,4 glucuronyltransferase I (transfers GlcA to XylRbo5P Rbo5PGalNAcGlcNAcMan6P) | Golgi | MDDGA13 | AR | 23359570 |
| LARGE1 | 603590 | β1–3 GlcA-transferase/α1–3 Xyl-transferase (transfers GlcAXyl to GlcAXylRbo5P Rbo5PGalNAcGlcNAcMan6P) | Golgi | MDDGA6, MDDGB6 | AR | 12966029 |
| O-xylosylation and glycosaminoglycan synthesis | ||||||
| XYLT1 | 608124 | Xyl-transferase 1 | Golgi | Desbuquois dysplasia type 2 | AR | 23982343 |
| XYLT2 | 608125 | Xyl-transferase 2 | Golgi | Spondyloocular syndrome | AR | 26027496 |
| B4GALT7 | 604327 | β1–4 Gal-transferase I (transfers galactose to Xyl) | Golgi | Progeroid EDS 1 (Larsen of Reunion Island syndrome) | AR | 10473568, 10506123 |
| B3GALT6 | 615291 | β1–3 Gal-transferase II (transfers Gal to GalXyl) | Golgi | SEMDJL Beighton type (progeroid EDS type 2) | AR | 23664117 |
| B3GAT3 | 606374 | β1–3 GlcA-transferase I (transfers GlcA to GalGalXyl to create linker tetrasaccharide) | Golgi | Larsen-like syndrome | AR | 21763480 |
| EXT1 | 608177 | β1–4 GlcA-transferase II / α1–4 GlcNAc-transferase II (HS polymerase) | Golgi | Multiple hereditary exostoses type 1 | AD | 7550340 |
| EXT2 | 608210 | β1–4 GlcA-transferase II / α1–4 GlcNAc-transferase II (HS polymerase) | Golgi | Multiple hereditary exostoses type 2; seizures, scoliosis and macrocephaly syndrome | AD; AR | 8782816; 26246518 |
| EXTL3 | 605744 | α1–4 GlcNAc-transferase I (transfers first GlcNAc to linker for HS initiation) and II (HS elongation) | Golgi | Immunoskeletal dysplasia with neurodevelopmental abnormalities | AR | 28132690, 28148688 |
| CHSY1 | 608183 | β1–3 GlcA-transferase/ β1–4 GalNAc-transferase (CS elongation) | Golgi | Temtamy preaxial brachydactyly syndrome | AR | 21129728 |
| CHST3 | 603799 | GalNAc-6-O-sulfotransferase (CS modification) | Golgi |
| AR | 15215498 |
| CHST11 | 610128 | GalNAc-4-O-sulfotransferase (CS modification) | Golgi | Chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly | AR | 29514872 |
| CHST14 | 608429 | GalNAc-4-O-sulfotransferase (DS modification) | Golgi | EDS musculocontractural type 1 | AR | 20004762 |
| DSE | 605942 | Converts D-glucuronic acid to L-iduronic acid (DS epimerase) | Golgi | EDS musculocontractural type 2 | AR | 23704329 |
| CSGALNACT1 | 616615 | β1–4 GalNAc-transferase I (transfers first GalNAc to linker for CS initiation) | Golgi | Desbuquois dysplasia | AR | 27599773 |
| CHST6 | 605294 | GlcNAc-6-O-sulfotransferase (KS modification) | Golgi | Macular corneal dystrophy | AR | 11017086 |
| CANT1 | 613165 | UDP-Gal nucleotidase | ER and Golgi | Desbuquois dysplasia 1 | AR | 19853239 |
| SLC26A2 | 606718 | Sulfate transporter | Plasma membrane | Achondrogenesis type 1; atelosteogenesis type 2; diastrophic dysplasia; multiple epiphyseal dysplasia type 4 | AR | 7923357 |
| PAPSS2 | 603005 | Phosphoadenosine 5’-phosphosulfate synthetase | Cytosol | Spondyloepimetaphyseal dysplasia, Pakistani type | AR | 9771708 |
| IMPAD1 | 614010 | Golgi-resident phosphoadenosine phosphate phosphatase | Golgi | Chondrodysplasia with joint dislocations, gPAPP type | AR | 21549340 |
| SLC10A7 | 611459 | Transporter (unidentified substrate) | Plasma membrane |
| AR | 29878199; 30082715 |
| O-GalNAcylation | ||||||
| GALNT3 | 601756 | Polypeptide GalNAc-transferase | Golgi | Hyperphosphatemic familial tumoral calcinosis | AR | 15133511 |
| C1GALT1C1 | 300611 | Chaperone for the core 1 β1–3 galactosyltransferase | ER | Tn polyagglutination syndrome | Somatic | 16251947 |
| O-GlcNAcylation | ||||||
| OGT | 300255 | O-GlcNAc-transferase | Nucleus and cytosol | MRX106 | XL | 28302723, 28584052 |
| EOGT | 614789 | EGF-domain O-GlcNAc-transferase | ER | Adams–Oliver syndrome 4 | AR | 23522784 |
| ST3GAL3 | 606494 | α2–3 Sia-transferase (transfers Sia to Lewis a trisaccharide) | Golgi | MRT12; EIEE15 | AR | 21907012; 23252400 |
| O-glucosylation | ||||||
| POGLUT1 | 615618 | Protein O-glucosyltransferase | ER | Dowling–Degos disease 4; LGMD2Z | AD; AR | 24387993; 27807076 |
| O-fucosylation | ||||||
| POFUT1 | 607491 | Protein O-fucosyltransferase for EGF repeats | ER | Dowling–Degos disease 2 | AD | 23684010 |
| LFNG | 602576 | β1–3 GlcNAc-transferase (transfers GlcNAc to O-fucose on EGF repeats) | Golgi | Spondylocostal dysostosis type 3 | AR | 16385447 |
| B3GLCT | 610308 | β1–3 Glc-transferase (transfers Glc to O-fucose on TSR) | ER | Peters plus syndrome | AR | 16909395 |
| GPI biosynthesis defects | ||||||
| PIGA | 311770 | GlcNAc-transferase complex, catalytic subunit (transfers GlcNAc to PI) | ER (cytosolic side) | MCAHS2 (GPIBD4, EEIE20) | XL | 22305531 |
| PIGC | 601730 | GlcNAc-transferase complex | ER (cytosolic side) | PIGC-CDG | AR | 27694521 |
| PIGQ | 605754 | GlcNAc-transferase complex | ER (cytosolic side) | PIGQ-CDG | AR | 24463883 |
| PIGP | 605938 | GlcNAc-transferase complex | ER (cytosolic side) | EIEE55 (GPIBD14) | AR | 28334793 |
| PIGY | 610662 | GlcNAc-transferase complex | ER (cytosolic side) | HPMRS6 (GPIBD12) | AR | 26293662 |
| PIGH | 600154 | GlcNAc-transferase complex | ER (cytosolic side) | PIGH-CDG | AR | 29573052, 29603516 |
| PIGL | 605947 | GlcNAc-PI de-N-acetylase (GlcNAc-PI to GlcN-PI) | ER (cytosolic side) | CHIME syndrome (GPIBD5) | AR | 22444671 |
| PIGW | 610275 | Inositol acyltransferase (transfers fatty acid to GlcN-PI) | ER (luminal side) | HPMRS5 (GPIBD11) | AR | 24367057 |
| PIGM | 610273 | Man-transferase 1 (transfers Man to GlcN-aPI) | ER (luminal side) | GPIBD1 | AR | 16767100 |
| PIGV | 610274 | Man-transferase 2 (transfers Man to ManGlcN-aPI) | ER (luminal side) | HPMRS1 (GPIBD2) | AR | 20802478 |
| PIGN | 606097 | EtNP-transferase 1 (transfers EtNP to ManManGlcN-aPI) | ER (luminal side) | MCAHS1 (GPIBD3) | AR | 21493957 |
| PIGO | 614730 | EtNP-transferase 3 (transfers EtNP to ManMan(EtNP)ManGlcN-aPI) | ER (luminal side) | HPMRS2 (GPIBD6) | AR | 22683086 |
| PIGG | 616918 | EtNP-transferase 2 (transfers EtNP to EtNPManMan(EtNP) ManGlcN-aPI) | ER (luminal side) | MRT53 (GPIBD13) | AR | 26996948 |
| PIGT | 610272 | GPI transamidase (transfers protein to GPI anchor) | ER (luminal side) | MCAHS3 (GPIBD7) | AR | 23636107 |
| PIGS | 610271 | GPI transamidase (transfers protein to GPI anchor) | ER (luminal side) | AR | 30269814 | |
| GPAA1 | 603048 | GPI transamidase (transfers protein to GPI anchor) | ER (luminal side) | GPIBD15 | AR | 29100095 |
| PGAP1 | 611655 | Inositol deacylase (removes fatty acid) | ER (luminal side) | MRT42 (GPIBD9) | AR | 24784135 |
| PGAP3 | 611801 | Phospholipase A2 (removes unsaturated fatty acid at sn-2) | Golgi | HPMRS4 (GPIBD10) | AR | 24439110 |
| PGAP2 | 615187 | Reacylates sn-2 with stearic acid | Golgi | HPMRS3 (GPIBD8) | AR | 23561846, 23561847 |
| Glycolipid glycosylation | ||||||
| ST3GAL5 | 604402 | α2–3 Sia-transferase (GM3 synthase) | Golgi | Amish infantile epilepsy syndrome (salt and pepper syndrome) | AR | 15502825 |
| B4GALNT1 | 601873 | β1–4 GalNAc-transferase (GM2/GD2 synthase) | Golgi | SPG26 | AR | 23746551 |
| A4GALT | 607922 | α1–4 Gal-transferase (GB3 synthase) | Golgi | NOR polyagglutination syndrome | AD | 22965229 |
| Disorders of multiple pathways | ||||||
| Monosaccharide synthesis | ||||||
| GFPT1 | 138292 | Glutamine:F6P amidotransferase (coverts F6P to GlcN-6P for UDP-GlcNAc synthesis) | Cytosol | CMS12 | AR | 21310273 |
| GNE | 603824 | UDP-GlcNAc 2-epimerase/ManNac kinase (converts UDP-GlcNAc to ManNac and then to ManNac-6P) | Cytosol | GNE myopathy; sialuria | AR; AD | 11528398; 10330343 |
| NANS | 605202 | Converts ManNac6P to Neu5Ac-9P | Cytosol | SEMD, Camera–Genevieve type | AR | 27213289 |
| Monosaccharide interconversion | ||||||
| PGM1 | 612934 | Phosphoglucomutase (reversible conversion of Glc-1P to Glc-6P) | Cytosol | PGM1-CDG (CDG-It) | AR | 19625727 |
| PGM3 | 172100 | Reversible conversion of GlcNAc-6P to GlcNAc-1P | Cytosol | Immunodeficiency 23 | AR | 24589341, 24698316, 24931394 |
| G6PC3 | 611045 | Glucose-6-phosphatase (Glc-6-P to Glc) | ER | Severe congenital neutropenia 4 | AR | 19118303 |
| Dolichol biosynthesis | ||||||
| DHDDS | 608172 | Cis-isoprenyltransferase | ER (cytosolic side) | Retinitis pigmentosa 59 | AR, AD | 21295283 |
| NUS1 | 610463 | Stabilizes cis-isoprenyltransferase | ER | NUS1-CDG (CDG-Iaa) | AR, AD | 25066056 |
| SRD5A3 | 611715 | Polyprenol reductase | ER | SRD5A3-CDG (CDG-Iq) | AR | 20637498 |
| DOLK | 610746 | Dolichol kinase | ER | DOLK-CDG (CDG-Im) | AR | 17273964 |
| Dolichol-P-sugar biosynthesis and utilization | ||||||
| DPM1 | 603503 | Dol-P-Man synthase | ER (cytosolic side) | DPM1-CDG (CDG-Ie) | AR | 10642597, 10642602 |
| DPM2 | 603564 | Dol-P-Man synthase | ER | DPM2-CDG (CDG-Iu) | AR | 23109149 |
| DPM3 | 605951 | Dol-P-Man synthase | ER | DPM3-CDG (CDG-Io) | AR | 19576565 |
| MPDU1 | 604041 | Dol-P-sugar availability | ER | MPDU1-CDG (CDG-If) | AR | 11733564 |
| Nucleotide-sugar synthesis | ||||||
| CAD | 114010 | First 3 enzymes in pyrimidine biosynthesis | Cytosol | CAD-CDG (CDG-Iz, EEIE50) | AR | 25678555 |
| GMPPA | 615495 | Regulatory role or GMPPB | Cytosol | Alacrima, achalasia, and intellectual deficiency syndrome | AR | 24035193 |
| GMPPB | 615320 | Synthesizes GDP-mannose from Man-1-P and GTP | Cytosol | MDDGA14, MDDGB14, MDDGC14 | AR | 23768512 |
| Transporters | ||||||
| SLC35A1 | 605634 | CMP-Sia transport | Golgi | SLC35A1-CDG (CDG-IIf) | AR | 15576474 |
| SLC35A2 | 314375 | UDP-Galactose transport | Golgi | SLC35A2-CDG (EIEE22) | XL | 23561849 |
| SLC35A3 | 605632 | UDP-GlcNAc transport | Golgi | SLC35A3-CDG | AR | 24031089 |
| SLC35C1 | 605881 | GDP-Fuc transport | Golgi | SLC35C1-CDG (CDG-IIc) | AR | 11326279 |
| SLC35D1 | 610804 | UDP-GlcA/UDP-GalNAc transport | Golgi | Schneckenbecken dysplasia | AR | 17952091 |
| SLC39A8 | 608732 | Cation transporter | Plasma membrane | SLC39A8-CDG (CDG-IIn) | AR | 26637978, 26637979 |
| Vesicular trafficking | ||||||
| COG1 | 606973 | Golgi-to-ER retrograde transport | Vesicular membrane/cytosol | COG1-CDG (CDG-IIg) | AR | 16537452 |
| COG2 | 606974 | Golgi-to-ER retrograde transport | Vesicular membrane/cytosol | COG2-CDG (CDG-IIq) | AR | 24784932 |
| COG4 | 606976 | Golgi-to-ER retrograde transport | Vesicular membrane/cytosol | COG4-CDG (CDG-IIj, AR), Saul–Wilson disease (AD) | AR, AD | 19494034 |
| COG5 | 606821 | Golgi-to-ER retrograde transport | Vesicular membrane/cytosol | COG5-CDG (CDG-IIi) | AR | 19690088 |
| COG6 | 606977 | Golgi-to-ER retrograde transport | Vesicular membrane/cytosol | COG6-CDG (CDG-IIl – 2L), Shaheen syndrome | AR | 20605848 |
| COG7 | 606978 | Golgi-to-ER retrograde transport | Vesicular membrane/cytosol | COG7-CDG (CDG-IIe) | AR | 15107842 |
| COG8 | 606979 | Golgi-to-ER retrograde transport | Vesicular membrane/cytosol | COG8-CDG (CDG-IIh) | AR | 17220172 |
| COPA | 601924 | COP-I subunit alpha (Golgi-to-ER transport) | Vesicular membrane/cytosol | Autoimmune interstitial lung, joint, and kidney disease | AD | 25894502 |
| COPB2 | 606990 | COP-I subunit beta-2 (Golgi-to-ER transport) | Vesicular membrane/cytosol | Primary microcephaly | AR | 29036432 |
| ARCN1 | 600820 | COP-I subunit delta (Golgi-to-ER transport) | Vesicular membrane/cytosol | Rhizomelic short stature with microcephaly, micrognathia, and developmental delay | AD | 27476655 |
| SEC23A | 610511 | COP-II component (ER-to-Golgi transport) | Vesicular membrane/cytosol | Craniolenticulosutural dysplasia (Boyadjiev–Jabs syndrome) | AR | 16980979 |
| SEC23B | 610512 | COP-II component (ER-to-Golgi transport) | Vesicular membrane/cytosol | Congenital dyserythropoietic anemia type II; Cowden syndrome 7 | AR; AD | 19561605, 19621418, 26522472 |
| SEC24D | 607186 | COP-II component (ER-to-Golgi transport) | Vesicular membrane/cytosol | Cole-Carpenter syndrome 2 | AR | 25683121 |
| SAR1B | 607690 | COP-II GTPase (ER-to-Golgi transport) | Vesicular membrane/cytosol | Chylomicron retention disease | AR | 12692552 |
| JAGN1 | 616012 | COP interactor | Vesicular membrane/cytosol | Severe congenital neutropenia type 6 | AR | 25129144 |
| TRIP11 | 604505 | Anterograde and retrograde transport | cis-Golgi | Achondrogenesis IA; odontochondrodysplasia | AR | 20089971 |
| TRAPPC2 | 300202 | Subunit of TRAPP tethering complex | Vesicular membrane/cytosol | SED tarda | XL | 10431248 |
| TRAPPC6B | 610397 | Subunit of TRAPP tethering complex | Vesicular membrane/cytosol | TRAPPC8B-CDG | AR | 28626029 |
| TRAPPC9 | 611966 | Subunit of TRAPP tethering complex | Vesicular membrane/cytosol | MRT13 | AR | 20004763, 20004764, 20004765 |
| TRAPPC11 | 614138 | Subunit of TRAPP tethering complex | Vesicular membrane/cytosol | LGMD2S | AR | 23830518 |
| TRAPPC12 | 614139 | Subunit of TRAPP tethering complex | Vesicular membrane/cytosol | TRAPPC12-CDG | AR | 28777934 |
| VPS13B | 607817 | Subunit of VPS13 complex | Vesicular membrane/cytosol | Cohen syndrome | AR | 12730828 |
| GOSR2 | 604027 | SNARE protein | Vesicular membrane/cytosol | Progressive myoclonic epilepsy type 6 | AR | 21549339 |
| Golgi homeostasis | ||||||
| ATP6V0A2 | 611716 | pH (subunit of vacuolar ATPase) | Vacuolar membrane | Autosomal recessive cutis laxa type IIA (wrinkly skin syndrome) | AR | 18157129 |
| ATP6AP1 | 300197 | pH (subunit of vacuolar ATPase) | Vacuolar membrane | Immunodeficiency 47 | XL | 27231034 |
| ATP6AP2 | pH (subunit of vacuolar ATPase) | Vacuolar membrane | X-linked intellectual deficiency, Hedera type | XL | 15746149 | |
| ATP6V1A | 607027 | pH (subunit of vacuolar ATPase) | Vacuolar membrane | Autosomal recessive cutis laxa type IID | AR | 28065471 |
| ATP6V1E1 | 108746 | pH (subunit of vacuolar ATPase) | Vacuolar membrane | Autosomal recessive cutis laxa type IIC | AR | 28065471 |
| TMEM199 | 616815 | Assembly factor for vacuolar ATPase | Vacuolar membrane | TMEM199-CDG (CDG-IIp) | AR | 26833330 |
| CCDC115 | 613734 | Assembly factor for vacuolar ATPase | Vacuolar membrane | CCDC115-CDG (CDG-Ip) | AR | 26833332 |
| VMA21 | 300913 | Assembly factor for vacuolar ATPase | Vacuolar membrane | X-linked myopathy with excessive autophagy | XL | 23315026 |
| TMEM165 | 614726 | pH, manganese and calcium homeostasis | Golgi | TMEM165-CDG (CDG-IIk) | AR | 22683087 |
| SLC9A7 | 300368 | pH homeostasis | Golgi | SLC9A7-CDG | XLR | 30335141 |
| Deglycosylation | ||||||
| NGLY1 | 610661 | Cleaves glycan chain from asparagine | Cytosol | NGLY1-CDG | AR | 22581936 |
| Unknown | ||||||
| TGDS | 616146 | TDP-Glc 4,6-dehydratase | Unknown | Catel-Manzke syndrome | AR | 25480037 |
Abbreviations: AD, autosomal-dominant; AR, autosomal-recessive; CMS, congenital myasthenic syndrome; CS, chondroitin sulfate; DS, dermatan sulfate; EDS, Ehlers–Danlos syndrome; EGF, epidermal growth factor-like; EIEE, early-infantile epileptic encephalopathy; EtNP, Ethanolamine phosphate; F6P, fructose 6-phosphate; GPIBD, glycosylphosphatidylinositol biosynthesis defect; HPMRS, hyperphosphatasia with mental retardation syndrome; HS, heparin sulfate; KS, keratan sulfate; LGMD, limb-girdle muscular dystrophy; MCAHS, multiple congenital anomalies-hypotonia-seizures syndrome; MDDG, muscular dystrophy-dystroglycanopathy; MRT, “mental retardation”; Neu5Ac, N-aceteylneuraminic acid; PI, phosphatidylinositol; OST, oligosaccharyltransferase; RP, retinitis pigmentosa; SED, spondyloepiphyseal dysplasia; SEMDJL, spondyloepimetaphyseal dysplasia with joint laxity; SPG, spastic paraplegia; TSR, thrombospondin type 1 repeats; XL, X-linked.
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