Congenital disorder of glycosylation

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Congenital disorders of glycosylation
Specialty Neurology

A congenital disorder of glycosylation (previously called carbohydrate-deficient glycoprotein syndrome) is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. Congenital disorders of glycosylation are sometimes known as CDG syndromes. They often cause serious, sometimes fatal, malfunction of several different organ systems (especially the nervous system, muscles, and intestines) in affected infants. [1] The most common sub-type is PMM2-CDG (formerly known as CDG-Ia) where the genetic defect leads to the loss of phosphomannomutase 2 (PMM2), the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate. [2]

Contents

Presentation

Clinical features depend on the molecular pathology of the particular CDG subtype. Common manifestations include ataxia; seizures; retinopathy; liver disease; coagulopathies; failure to thrive (FTT); dysmorphic features (e.g., inverted nipples and subcutaneous fat pads); pericardial effusion, skeletal abnormalities, and hypotonia. If an MRI is obtained, cerebellar hypoplasia is a common finding. [3] Some CDG subtypes, like SSR4-CDG 1y, have been classified as connective tissue disorders. [4]

Ocular abnormalities of PMM2-CDG include: myopia, infantile esotropia, delayed visual maturation, peripheral neuropathy (PN), strabismus , nystagmus , optic disc pallor, and reduced rod function on electroretinography. [5] Three CDG subtypes PMM2-CDG, PMI-CDG, ALG6-CDG can cause congenital hyperinsulinism with hyperinsulinemic hypoglycemia in infancy. [6] Because glycoproteins are involved in many central nervous system processes important during early development, intellectual disability and developmental delays are also common in CDG [7]

N-Glycosylation and known defects

A biologically very important group of carbohydrates is the asparagine (Asn)-linked, or N-linked, oligosaccharides. Their biosynthetic pathway is very complex and involves a hundred or more glycosyltransferases, glycosidases, transporters and synthases. This plethora allows for the formation of a multitude of different final oligosaccharide structures, involved in protein folding, intracellular transport/localization, protein activity, and degradation/half-life. A vast amount of carbohydrate binding molecules (lectins) depend on correct glycosylation for appropriate binding; the selectins, involved in leukocyte extravasation, is a prime example. Their binding depends on a correct fucosylation of cell surface glycoproteins. Lack thereof leads to leukocytosis and increased sensitivity to infections as seen in SLC35C1-CDG(CDG-IIc); caused by a GDP-fucose (Fuc) transporter deficiency. [8] All N-linked oligosaccharides originate from a common lipid-linked oligosaccharide (LLO) precursor, synthesized in the ER on a dolichol-phosphate (Dol-P) anchor. The mature LLO is transferred co-translationally to consensus sequence Asn residues in the nascent protein, and is further modified by trimming and re-building in the Golgi. [9]

Deficiencies in the genes involved in N-linked glycosylation constitute the molecular background of most CDGs. [10]

Type I

DescriptionDisorderProduct
The formation of the LLO is initiated by the synthesis of the polyisoprenyl dolichol from farnesyl, a precursor of cholesterol biosynthesis. This step involves at least three genes, DHDDS (encoding dehydrodolichyl diphosphate synthase that is a cis-prenyl transferase), DOLPP1 (a pyrophosphatase) and SRD5A3, encoding a reductase that completes the formation of dolichol.Recently, exome sequencing showed that mutations in DHDDS cause a disorder with a retinal phenotype (retinitis pigmentosa, a common finding in CDG patients. [11] Further, the intermediary reductase in this process (encoded by SRD5A3), is deficient in SRD5A3-CDG (CDG-Iq). [12]
Doichol.png
Dol is then activated to Dol-P via the action of Dol kinase in the ER membrane.This process is defective in DOLK-CDG (CDG-Im). [13]
Dolichol monophosphate.svg
Consecutive N-acetylglucosamine (GlcNAc)- and mannosyltransferases use the nucleotide sugar donors UDP-GlcNAc and GDP-mannose (Man) to form a pyrophosphate-linked seven sugar glycan structure (Man5GlcNAc2-PP-Dol) on the cytoplasmatic side of the ER.Some of these steps have been found deficient in patients.
  • Deficiency in GlcNAc-1-P transferase causes DPAGT1-CDG (CDG-Ij) [14]
  • Loss of the first mannosyltransferase causes ALG1-CDG (CDG-Ik) [15]
  • Loss of the second mannosyltransferase (adds Man II and III) causes ALG2-CDG (CDG-Ii). [16]
  • Loss of the third mannosyltransferase (adds Man IV and V) causes ALG11-CDG (CDG-Ip) [17]
  • Mutations in the other genes involved in these steps (ALG13 and ALG14) are yet to be described.
Man5GlcNAc2-PP-Dol
The M5GlcNAc2-structure is then flipped to the ER lumen, via the action of a "flippase"This is deficient in RFT1-CDG (CDG-In). [18]
Finally, three mannosyltransferases and three glucosyltransferases complete the LLO structure Glc3Man9GlcNAc2-PP-Dol using Dol-P-Man and Dol-P-glucose (Glc) as donors.There are five known defects:
  • mannosyltransferase VI deficiency causes ALG3-CDG (CDG-Id) [19]
  • mannosyltransferase VII/IX deficiency causes ALG9-CDG (CDG-IL) [20]
  • mannosyltransferase VIII deficiency causes ALG12-CDG (CDG-Ig) [21]
  • glucosyltransferase I deficiency causes ALG6-CDG (CDG-Ic) [22]
  • glucosyltransferase II deficiency causes ALG8-CDG (CDG-Ih). [23]
Glc3Man9GlcNAc2-PP-Dol
A protein with hitherto unknown activity, MPDU-1, is required for the efficient presentation of Dol-P-Man and Dol-P-Glc.Its deficiency causes MPDU1-CDG (CDG-If). [24]
The synthesis of GDP-Man is crucial for proper N-glycosylation, as it serves as donor substrate for the formation of Dol-P-Man and the initial Man5GlcNAc2-P-Dol structure. GDP-Man synthesis is linked to glycolysis via the interconversion of fructose-6-P and Man-6-P, catalyzed by phosphomannose isomerase (PMI).This step is deficient in MPI-CDG (CDG-Ib), [25] which is the only treatable CDG-I subtype.
Mannose-6-phosphate.svg
Man-1-P is then formed from Man-6-P, catalyzed by phosphomannomutase (PMM2), and Man-1-P serves as substrate in the GDP-Man synthesis.Mutations in PMM2 cause PMM2-CDG (CDG-Ia), the most common CDG subtype. [26]
Mannose-1-phosphate.svg
Dol-P-Man is formed via the action of Dol-P-Man synthase, consisting of three subunits; DPM1, DPM2, and DPM3.Mutations in DPM1 causes DPM1-CDG (CDG-Ie). Mutations in DPM2 (DPM2-CDG) and DPM3 (DPM3-CDG (CDG-Io)) [27] cause syndromes with a muscle phenotype resembling an a-dystroglycanopathy, possibly due to lack of Dol-P-Man required for O-mannosylation.
DolicholMPM.svg
The final Dol-PP-bound 14mer oligosaccharides (Glc3Man9GlcNAc2-PP-Dol) are transferred to consensus Asn residues in the acceptor proteins in the ER lumen, catalyzed by the oligosaccharyltransferase(OST). The OST is composed by several subunits, including DDOST, TUSC3, MAGT1, KRTCAP2 and STT3a and -3b.Three of these genes have hitherto been shown to be mutated in CDG patients, DDOST (DDOST-CDG (CDG-Ir)), TUSC3 (TUSC3-CDG) and MAGT1 (MAGT1-CDG).

Type II

The mature LLO chain is next transferred to the growing protein chain, a process catalysed by the oligosaccharyl transferase (OST) complex. [28]

Not all structures are fully modified, some remain as high-mannose structures, others as hybrids (one unmodified Man branch and one modified), but the majority become fully modified complex type oligosaccharides. [29]

In addition to glycosidase I, mutations have been found:[ citation needed ]

However, since at least 1% of the genome is involved in glycosylation, it is likely that many more defects remain to be found. [30]

Diagnosis

Classification

Historically, CDGs are classified as Types I and II (CDG-I and CDG-II), depending on the nature and location of the biochemical defect in the metabolic pathway relative to the action of oligosaccharyltransferase. The most commonly used screening method for CDG, analysis of transferrin glycosylation status by isoelectric focusing, ESI-MS, or other techniques, distinguish between these subtypes in so called Type I and Type II patterns. [31]

Currently, over 130 subtypes of CDG have been described. [32] [7]

Since 2009, most researchers use a different nomenclature based on the gene defect (e.g. CDG-Ia = PMM2-CDG, CDG-Ib = PMI-CDG, CDG-Ic = ALG6-CDG etc.). [33] The reason for the new nomenclature was the fact that proteins not directly involved in glycan synthesis (such as members of the COG-family [34] and vesicular H+-ATPase) [35] were found to be causing the glycosylation defect in some CDG patients.

Also, defects disturbing other glycosylation pathways than the N-linked one are included in this classification. Examples are the α-dystroglycanopathies (e.g. POMT1/POMT2-CDG (Walker-Warburg syndrome and Muscle-Eye-Brain syndrome)) with deficiencies in O-mannosylation of proteins; O-xylosylglycan synthesis defects (EXT1/EXT2-CDG (hereditary multiple exostoses) and B4GALT7-CDG (Ehlers-Danlos syndrome, progeroid variant)); O-fucosylglycan synthesis (B3GALTL-CDG (Peter's plus syndrome) and LFNG-CDG (spondylocostal dysostosis III)). [36]

Type I

  • Type I disorders involve disrupted synthesis of the lipid-linked oligosaccharide precursor (LLO) or its transfer to the protein.

Types include:

Type OMIM Gene Locus
Ia (PMM2-CDG) 212065 PMM2 16p13.3-p13.2
Ib (MPI-CDG) 602579 MPI 15q22-qter
Ic (ALG6-CDG) 603147 ALG6 1p22.3
Id (ALG3-CDG) 601110 ALG3 3q27
Ie (DPM1-CDG) 608799 DPM1 20q13.13
If (MPDU1-CDG) 609180 MPDU1 17p13.1-p12
Ig (ALG12-CDG) 607143 ALG12 22q13.33
Ih (ALG8-CDG) 608104 ALG8 11pter-p15.5
Ii (ALG2-CDG) 607906 ALG2 9q22
Ij (DPAGT1-CDG) 608093 DPAGT1 11q23.3
Ik (ALG1-CDG) 608540 ALG1 16p13.3
1L (ALG9-CDG) 608776 ALG9 11q23
Im (DOLK-CDG) 610768 DOLK 9q34.11
In (RFT1-CDG) 612015 RFT1 3p21.1
Io (DPM3-CDG) 612937 DPM3 1q12-q21
Ip (ALG11-CDG) 613661 ALG11 13q14.3
Iq (SRD5A3-CDG) 612379 SRD5A3 4q12
Ir (DDOST-CDG) 614507 DDOST 1p36.12
It (PGM1-CDG)

(formerly GSD-XIV)

Phosphoglucomutase deficiency

614921 PGM1 1p31.3
DPM2-CDG n/a DPM2 9q34.13
TUSC3-CDG 611093 TUSC3 8p22
MAGT1-CDG 300716 MAGT1 X21.1
DHDDS-CDG 613861 DHDDS 1p36.11
I/IIx 212067 n/an/a

Type II

  • Type II disorders involve malfunctioning trimming/processing of the protein-bound oligosaccharide chain.

Types include:

Type OMIM Gene Locus
IIa (MGAT2-CDG) 212066 MGAT2 14q21
IIb (GCS1-CDG) 606056 GCS1 2p13-p12
IIc (SLC335C1-CDG; Leukocyte adhesion deficiency II)) 266265 SLC35C1 11p11.2
IId (B4GALT1-CDG) 607091 B4GALT1 9p13
IIe (COG7-CDG) 608779 COG7 16p
IIf (SLC35A1-CDG) 603585 SLC35A1 6q15
IIg (COG1-CDG) 611209 COG1 17q25.1
IIh (COG8-CDG) 611182 COG8 16q22.1
IIi (COG5-CDG) 613612 COG5 7q31
IIj (COG4-CDG) 613489 COG4 16q22.1
IIL (COG6-CDG) n/a COG6 13q14.11
IIT (CDG2T) 618885 GALNT2
ATP6V0A2-CDG (autosomal recessive cutis laxa type 2a (ARCL-2A)) 219200 ATP6V0A2 12q24.31
MAN1B1-CDG (Mental retardation, autosomal recessive 15) 614202 MAN1B1 9q34.3
ST3GAL3-CDG (Mental retardation, autosomal recessive 12) 611090 ST3GAL3 1p34.1

Disorders of O-mannosylation

Mutations in several genes have been associated with the traditional clinical syndromes, termed muscular dystrophy-dystroglycanopathies (MDDG). A new nomenclature based on clinical severity and genetic cause was recently proposed by OMIM. [37] The severity classifications are A (severe), B (intermediate), and C (mild). The subtypes are numbered one to six according to the genetic cause, in the following order: (1) POMT1, (2) POMT2, (3) POMGNT1, (4) FKTN, (5) FKRP, and (6) LARGE. [38]

Most common severe types include:

Name OMIM Gene Locus
POMT1-CDG (MDDGA1;Walker-Warburg syndrome) 236670 POMT1 9q34.13
POMT2-CDG (MDDGA2;Walker-Warburg syndrome) 613150 POMT2 14q24.3
POMGNT1-CDG (MDDGA3; Muscle-eye-brain) 253280 POMGNT1 1p34.1
FKTN-CDG (MDDGA4; Fukuyama congenital muscular dystrophy) 253800 FKTN 9q31.2
FKRP-CDG (MDDGB5; MDC1C) 606612 FKRP 19q13.32
LARGE-CDG (MDDGB6; MDC1D) 608840 LARGE 22q12.3

Treatment

No treatment is available for most of these disorders. Mannose supplementation relieves the symptoms in MPI-CDG for the most part, [39] even though the hepatic fibrosis may persist. [40] Fucose supplementation has had a partial effect on some SLC35C1-CDG patients. [41]

In 2024, it was reported that a study suggested that Ibuprofen might be helpful as a treatment for one such genetic disease. [42]

History

The first CDG patients (twin sisters) were described in 1980 by Jaeken et al. [43] Their main features were psychomotor retardation, cerebral and cerebellar atrophy and fluctuating hormone levels (e.g.prolactin, FSH and GH). During the next 15 years the underlying defect remained unknown but since the plasmaprotein transferrin was underglycosylated (as shown by e.g.isoelectric focusing), the new syndrome was named carbohydrate-deficient glycoprotein syndrome (CDGS) [1] Its "classic" phenotype included psychomotor retardation, ataxia, strabismus, anomalies (fat pads and inverted nipples) and coagulopathy.[ citation needed ]

In 1994, a new phenotype was described and named CDGS-II. [44] In 1995, Van Schaftingen and Jaeken showed that CDGS-I (now PMM2-CDG) was caused by the deficiency of the enzyme phosphomannomutase. This enzyme is responsible for the interconversion of mannose-6-phosphate and mannose-1-phosphate, and its deficiency leads to a shortage in GDP-mannose and dolichol (Dol)-mannose (Man), two donors required for the synthesis of the lipid-linked oligosaccharide precursor of N-linked glycosylation. [45]

In 1998, Niehues described a new CDG syndrome, MPI-CDG, which is caused by mutations in the enzyme metabolically upstream of PMM2, phosphomannose isomerase (PMI). [25] A functional therapy for MPI-CDG, alimentary mannose was also described. [25]

The characterization of new defects took increased and several new Type I and Type II defects were delineated. [46]

In 2012, Need described the first case of a congenital disorder of deglycosylation, NGLY1 deficiency. [47] A 2014 study of NGLY1 deficient patients found similarities with traditional congenital disorders of glycosylation. [48]

See also

Related Research Articles

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule in order to form a glycoconjugate. In biology, glycosylation usually refers to an enzyme-catalysed reaction, whereas glycation may refer to a non-enzymatic reaction.

<span class="mw-page-title-main">PMM2</span> Protein-coding gene in the species Homo sapiens

Phosphomannomutase 2 is an enzyme that in humans is encoded by the PMM2 gene.

<span class="mw-page-title-main">ALG6</span> Protein-coding gene in the species Homo sapiens

Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase is an enzyme that in humans is encoded by the ALG6 gene.

<span class="mw-page-title-main">DPAGT1</span> Protein-coding gene in the species Homo sapiens

UDP-N-acetylglucosamine—dolichyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme that in humans is encoded by the DPAGT1 gene.

<span class="mw-page-title-main">ALG2</span> Protein-coding gene in the species Homo sapiens

Alpha-1,3/1,6-mannosyltransferase ALG2 is an enzyme that is encoded by the ALG2 gene. Mutations in the human gene are associated with congenital defects in glycosylation The protein encoded by the ALG2 gene belongs to two classes of enzymes: GDP-Man:Man1GlcNAc2-PP-dolichol alpha-1,3-mannosyltransferase and GDP-Man:Man2GlcNAc2-PP-dolichol alpha-1,6-mannosyltransferase.

<span class="mw-page-title-main">B4GALT7</span> Protein-coding gene in the species Homo sapiens

Beta-1,4-galactosyltransferase 7 also known as galactosyltransferase I is an enzyme that in humans is encoded by the B4GALT7 gene. Galactosyltransferase I catalyzes the synthesis of the glycosaminoglycan-protein linkage in proteoglycans. Proteoglycans in turn are structural components of the extracellular matrix that is found between cells in connective tissues.

<span class="mw-page-title-main">DPM1</span> Protein-coding gene in the species Homo sapiens

Dolichol-phosphate mannosyltransferase is an enzyme that in humans is encoded by the DPM1 gene.

<span class="mw-page-title-main">MGAT2</span> Protein-coding gene in the species Homo sapiens

Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the MGAT2 gene.

<span class="mw-page-title-main">ALG12</span> Enzyme-coding gene in humans

Dolichyl-P-Man:Man(7)GlcNAc(2)-PP-dolichyl-alpha-1,6-mannosyltransferase is an enzyme that in humans is encoded by the ALG12 gene.

<span class="mw-page-title-main">ALG3</span> Protein-coding gene in the species Homo sapiens

Dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase is an enzyme that, in humans, is encoded by the ALG3 gene.

<span class="mw-page-title-main">ALG1</span> Protein-coding gene in the species Homo sapiens

Chitobiosyldiphosphodolichol beta-mannosyltransferase is an enzyme that is encoded by ALG1 whose structure and function has been conserved from lower to higher organisms.

<span class="mw-page-title-main">Dehydrodolichyl diphosphate synthase</span> Enzyme found in humans

Dehydrodolichyl diphosphate synthase is an enzyme that in humans is encoded by the DHDDS gene.

<span class="mw-page-title-main">DPM3</span> Protein-coding gene in the species Homo sapiens

dolichyl-phosphate mannosyltransferase polypeptide 3, also known as DPM3, is a human gene.

<span class="mw-page-title-main">ALG8 (enzyme class)</span> Class of enzymes

Dolichyl-P-Glc:Glc1Man9GlcNAc2-PP-dolichol alpha-1,3-glucosyltransferase is an enzyme with systematic name dolichyl beta-D-glucosyl phosphate:D-Glc-alpha-(1->3)-D-Man-alpha-(1->2)-D-Man-alpha-(1->2)-D-Man-alpha-(1->3)-(D-Man-alpha- -D-Man-alpha- - -D-Man-alpha- )-D-Man-beta-(1->4)-D-GlcNAc-beta-(1->4)-D-GlcNAc-diphosphodolichol alpha-1,3-glucosyltransferase.

PGM3 deficiency is a rare genetic disorder of the immune system associated with diminished phosphoglucomutase 3 function. PGM3 is an enzyme which in humans is encoded by gene PGM3. This disorder manifests as severe atopy, immune deficiency, autoimmunity, intellectual disability, and hypomyelination. In 2014, Investigators Atfa Sassi at the Pasteur Institute of Tunis, Sandra Lazaroski at the University Medical Center Freiburg, and Gang Wu at the Imperial College London, identified PGM3 mutations in nine patients from four consanguineous families. In the same year, a researchers from the laboratories of Joshua Milner and Helen Su at the National Institute of Allergy and Infectious Disease at the U.S. National Institutes of Health described PGM3 deficiency in eight additional patients from two families.

<span class="mw-page-title-main">Harry Schachter</span> Canadian biochemist (1933–2024)

Harry Schachter FRSC was a Canadian biochemist and glycobiologist. He was professor at the University of Toronto and at the Hospital For Sick Children in Toronto.

<span class="mw-page-title-main">PMM2 deficiency</span> Medical condition

PMM2 deficiency or PMM2-CDG, previously CDG-Ia, is a very rare genetic disorder caused by mutations in PMM2. It is an autosomal recessive disease that is the most common type of congenital disorder of glycosylation or CDG. PMM2-CDG is the most common of a growing family of more than 130 extremely rare inherited metabolic disorders. Only about 800 children and adults have been reported worldwide.

<span class="mw-page-title-main">MPI-CDG</span> Medical condition

MPI-CDG is an autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in MPI. The clinical symptoms in MPI-CDG are caused by deficient activity of the enzyme mannose phosphate isomerase. Clinically, the most common symptoms of MPI-CDG are chronic diarrhea, failure to thrive, protein-losing enteropathy, and coagulopathy. MPI-CDG differs from most other described glycosylation disorders due to its lack of central nervous system involvement, and because it has treatment options besides supportive care. Treatment with oral mannose has been shown to improve most symptoms of the disease. If left untreated, MPI-CDG can be fatal. MPI-CDG was previously known as CDG-IB. The disorder was first described clinically in 1986, and the underlying genetic defect was identified in 1998.

<span class="mw-page-title-main">SRD5A3-CDG</span> Medical condition

SRD5A3-CDG is a rare, non X-linked congenital disorder of glycosylation (CDG) due to a mutation in the steroid 5 alpha reductase type 3 gene. It is one of over 150 documented types of Congenital disorders of Glycosylation. Like many other CDGs, SRD5A3 is ultra-rare, with around 38 documented cases in the world.

References

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  9. ↑ Breitling, J.; Aebi, M. (2013). "N-Linked Protein Glycosylation in the Endoplasmic Reticulum". Cold Spring Harbor Perspectives in Biology. 5 (8): a013359. doi:10.1101/cshperspect.a013359. PMC   3721281 . PMID   23751184.
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