Chapter 19 – Disorders of Glycosylation and Movement Disorders




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.





Chapter 19 Disorders of Glycosylation and Movement Disorders


Eva Morava , Carlos R. Ferreira , and Marc Patterson



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.




Table 19.1 Overview of the CDGs














































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































Gene Gene locus OMIM number Function Localization of defect Disease Inheritance Initial molecular characterization (PMID)
N-linked glycosylation defects
Interconversion of monosaccharides
PMM2 601785


  • Phosphomannomutase



  • (converts Man-6-P to Man-1-P)

Cytosol PMM2-CDG (CDG-Ia) AR 9140401
MPI 154550


  • Phosphomannose isomerase



  • (converts Fru-6-P to Man-6-P)

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


  • β1-4 xylosyltransferase



  • (transfers xylose to Rbo5P Rbo5PGalNAcGlcNAcMan6P)

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


  • SED with congenital joint



  • dislocations (AR Larsen syndrome, SED Omani type, humerospinal dysostosis)

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


  • Skeletal dysplasia with



  • amelogenesis imperfecta

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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Oct 19, 2020 | Posted by in NEUROLOGY | Comments Off on Chapter 19 – Disorders of Glycosylation and Movement Disorders

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