CDG syndrome
Encyclopedia
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
protein
s and/or lipid
s is deficient or defective. Congenital disorder
s of glycosylation are sometimes known as CDG syndrome
s. They often cause serious, sometimes fatal, malfunction of several different organ systems (especially the nervous system
, muscle
s, and intestine
s) in affected infants. The most common subtype is CDG-Ia (also referred to as PMM2-CDG) where the genetic defect leads to the loss of phosphomannomutase 2, the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate.
, 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 namned carbohydrate-deficient glycoprotein syndrome (CDGS). Its "classical" phenotype
included psychomotor retardation
, ataxia
, strabismus
, anomalies
(fat pads and inverted nipples) and coagulopathy
.
In 1994, a new phenotype was described and namned CDGS-II. In 1995, Van Schaftingen and Jaeken showed that CDGS-I (now CDG-Ia or 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-mannose, two donors required for the synthesis of the lipid-linked oligosaccharide precursor of N-linked glycosylation.
In 1998, Niehues et al. published a new CDG syndrome, CDG-Ib, which is caused by mutation
s in the enzyme metabolically upstream of PMM2, phosphomannose isomerase (PMI). In this paper, the authors also described a functional therapy for CDG-Ib, alimentary mannose.
The characterization of new defects took up speed and several new Type I and Type II defects were delineated.
relative to the action of oligosaccharyltransferase
.
Currently, seventeen CDG type-I variants have been identified and twelve variants of CDG Type-II have been described.
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). The reason for the new nomenclature was the fact that proteins not directly involved in glycan synthesis (such as members of the COG-family and vesicular H+-ATPase ) 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 as CDG syndromes.
Types include:
Types include:
! Type
! OMIM
! Gene
! Locus
>
|
| MGAT2
| 14q21>
|
| GCS1
| 2p13-p12>
|
| SLC35C1
| 11p11.2>
|
| B4GALT1
| 9p13>
|
| COG7
| 16p>
|
| SLC35A1
| 6q15>
|
| COG1
| 17q25.1>
|
| COG8
| 16q22.1>
|
| COG5
| 7q31>
|
| COG4
| 16q22.1>
; seizure
s; retinopathy
; liver
fibrosis; coagulopathies
; failure to thrive
; dysmorphic feature
s (e.g., inverted nipple
s and subcutaneous fat pad
s; and strabismus
. If an MRI is obtained, cerebellar atrophy and hypoplasia is a common finding.
Ocular abnormalities of CDG-Ia include: myopia
, infantile esotropia
, delayed visual maturation, low vision
, optic pallor, and reduced rod
function on electroretinography
.
Three subtypes of CDG I (a,b,d) can cause congenital hyperinsulinism
with hyperinsulinemic hypoglycemia
in infancy.
(Asn
)-linked, or N-linked, oligosaccharide
s. Their biosynthetic pathway is very complex and involves a hundred or more glycosyltransferase
s, glycosidases, transporter
s and synthase
s. 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 glycoprotein
s. Lack thereof leads to leukocytosis and increase sensitivity to infections as seen in SLC35C1-CDG(CDG-IIc); caused by a GDP-fucose (Fuc) transporter deficiency.
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
.
Deficiencies in the genes
involved in N-linked glycosylation
constitute the molecular background to most of the CDGs.
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.
In addition to glycosidase I, mutations have been found:
However, the use of >100 genes in this process, presumably means that many more defects are to be found.
supplementation relieves the symptoms in PMI-CDG (CDG-Ib) for the most part, even though the hepatic fibrosis may persist. Fucose
supplementation has had a partial effect on some SLC35C1-CDG (CDG-IIc or LAD-II) patients.
Glycosylation
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 biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
of a variety of tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s and/or lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s is deficient or defective. Congenital disorder
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
s of glycosylation are sometimes known as CDG syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
s. They often cause serious, sometimes fatal, malfunction of several different organ systems (especially the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
, muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
s, and intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
s) in affected infants. The most common subtype is CDG-Ia (also referred to as PMM2-CDG) where the genetic defect leads to the loss of phosphomannomutase 2, the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate.
History
The first CDG patients (twin sisters) were described in an abstract in the medical journal Pediatric Research in 1980 by Jaeken et al. Their main features were psychomotor retardationPsychomotor retardation
Psychomotor retardation involves a slowing-down of thought and a reduction of physical movements in an individual. Psychomotor retardation can cause a visible slowing of physical and emotional reactions, including speech and affect...
, cerebral
Cerebral atrophy
Cerebral atrophy is a common feature of many of the diseases that affect the brain. Atrophy of any tissue means loss of cells. In brain tissue, atrophy describes a loss of neurons and the connections between them...
and cerebellar atrophy and fluctuating hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
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 namned carbohydrate-deficient glycoprotein syndrome (CDGS). Its "classical" phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
included psychomotor retardation
Psychomotor retardation
Psychomotor retardation involves a slowing-down of thought and a reduction of physical movements in an individual. Psychomotor retardation can cause a visible slowing of physical and emotional reactions, including speech and affect...
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, strabismus
Strabismus
Strabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...
, anomalies
Congenital abnormality
A congenital anomaly is a condition which is present at the time of birth which varies from the standard presentation....
(fat pads and inverted nipples) and coagulopathy
Coagulopathy
Coagulopathy is a condition in which the blood’s ability to clot is impaired. This condition can cause prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.The normal clotting process depends on the interplay of various proteins in...
.
In 1994, a new phenotype was described and namned CDGS-II. In 1995, Van Schaftingen and Jaeken showed that CDGS-I (now CDG-Ia or PMM2-CDG) was caused by the deficiency of the enzyme phosphomannomutase
Phosphomannomutase
In enzymology, a phosphomannomutase is an enzyme that catalyzes the chemical reactionHence, this enzyme has one substrate, alpha-D-mannose 1-phosphate, and one product, D-mannose 6-phosphate....
. This enzyme is responsible for the interconversion of mannose-6-phosphate
Mannose-6-phosphate
Mannose-6-phosphate is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase....
and mannose-1-phosphate, and its deficiency leads to a shortage in GDP-mannose and dolichol-mannose, two donors required for the synthesis of the lipid-linked oligosaccharide precursor of N-linked glycosylation.
In 1998, Niehues et al. published a new CDG syndrome, CDG-Ib, which is caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the enzyme metabolically upstream of PMM2, phosphomannose isomerase (PMI). In this paper, the authors also described a functional therapy for CDG-Ib, alimentary mannose.
The characterization of new defects took up speed and several new Type I and Type II defects were delineated.
Classification
CDG can be classified as Types I and II (CDG-I and CDG-II), depending on the nature and location of the biochemical defect in the metabolic pathwayMetabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
relative to the action of oligosaccharyltransferase
Oligosaccharyltransferase
Oligosaccharyltransferase or OST is a membrane protein complex that transfers a 14-sugar oligosaccharide from dolichol to nascent protein. It is a type of glycosyltransferase...
.
Currently, seventeen CDG type-I variants have been identified and twelve variants of CDG Type-II have been described.
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). The reason for the new nomenclature was the fact that proteins not directly involved in glycan synthesis (such as members of the COG-family and vesicular H+-ATPase ) 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 as CDG syndromes.
Type I
- Type I disorders involve disrupted synthesis of the lipidLipidLipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
-linked oligosaccharideOligosaccharideAn oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...
precursor.
Types include:
Type II
- Type II disorders involve malfunctioning trimming/processing of the protein-bound oligosaccharide chain.
Types include:
! OMIM
! Gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
! Locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
>
|
| MGAT2
MGAT2
Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the MGAT2 gene.-External links:*...
| 14q21>
|
| GCS1
GCS1
Mannosyl-oligosaccharide glucosidase is an enzyme that in humans is encoded by the MOGS gene.GCS1 may also refer to "generative cell specific 1", also called HAP2 , a gene of lower eukaryotes which is thought to be responsible for gametes fusion ..-External links:*...
| 2p13-p12>
|
| SLC35C1
SLC35C1
GDP-fucose transporter 1 is a protein that in humans is encoded by the SLC35C1 gene.Defects can be associated with Congenital disorder of glycosylation type IIc.-External links:*...
| 11p11.2>
|
| B4GALT1
B4GALT1
Beta-1,4-galactosyltransferase 1 is an enzyme that in humans is encoded by the B4GALT1 gene.-External links:*...
| 9p13>
|
| COG7
COG7
Conserved oligomeric Golgi complex subunit 7 is a protein that in humans is encoded by the COG7 gene.-Interactions:COG7 has been shown to interact with COG4 and COG5.-External links:*...
| 16p>
|
| SLC35A1
SLC35A1
CMP-sialic acid transporter is a protein that in humans is encoded by the SLC35A1 gene.-External links:*...
| 6q15>
|
| COG1
COG1
Conserved oligomeric Golgi complex subunit 1 is a protein that in humans is encoded by the COG1 gene.-Interactions:COG1 has been shown to interact with COG4 and COG3.-External links:*...
| 17q25.1>
|
| COG8
COG8
Conserved oligomeric Golgi complex subunit 8 is a protein that in humans is encoded by the COG8 gene.-External links:*...
| 16q22.1>
|
| COG5
COG5
Conserved oligomeric Golgi complex subunit 5 is a protein that in humans is encoded by the COG5 gene.-Interactions:COG5 has been shown to interact with COG7 and COG4.-External links:*...
| 7q31>
|
| COG4
COG4
Conserved oligomeric Golgi complex subunit 4 is a protein that in humans is encoded by the COG4 gene.-Interactions:COG4 has been shown to interact with COG7, COG2, COG1 and COG5.-External links:*...
| 16q22.1>
Presentation
The specific problems produced differ according to the particular abnormal synthesis involved. Common manifestations include ataxiaAtaxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
; seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s; retinopathy
Retinopathy
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
; liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
fibrosis; coagulopathies
Coagulopathy
Coagulopathy is a condition in which the blood’s ability to clot is impaired. This condition can cause prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.The normal clotting process depends on the interplay of various proteins in...
; failure to thrive
Failure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
; dysmorphic feature
Dysmorphic feature
Dysmorphic feature is a medical term referring to a difference of body structure that is suggestive of a congenital disorder, genetic syndrome, or birth defect. A dysmorphic feature can be a minor and isolated birth defect...
s (e.g., inverted nipple
Inverted nipple
An inverted nipple is a condition where the nipple, instead of pointing outward, is retracted into the breast. In some cases, the nipple will be temporarily protruded if stimulated, but in others, the inversion remains regardless of stimulus...
s and subcutaneous fat pad
Fat pad
A fat pad is a mass of closely packed fat cells surrounded by fibrous tissue septa. They may be extensively supplied with capillaries and nerve endings.Examples are:* Intraarticular fat pads. These are also covered by a layer of synovial cells...
s; and strabismus
Strabismus
Strabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...
. If an MRI is obtained, cerebellar atrophy and hypoplasia is a common finding.
Ocular abnormalities of CDG-Ia include: myopia
Myopia
Myopia , "shortsightedness" ) is a refractive defect of the eye in which collimated light produces image focus in front of the retina under conditions of accommodation. In simpler terms, myopia is a condition of the eye where the light that comes in does not directly focus on the retina but in...
, infantile esotropia
Infantile esotropia
Infantile esotropia is an ocular condition of early onset in which one or either eye turns inward. It is a specific sub-type of esotropia and has been a subject of much debate amongst ophthalmologists with regard to its naming, diagnostic features, and treatment.- Name and features :Historically...
, delayed visual maturation, low vision
Low vision
Low vision is a subspecialty within the professions of optometry and ophthalmology dealing with individuals who have reduced vision even when using the best possible spectacle or contact lens correction available. It can be a result of either congenital disease Low vision is a subspecialty within...
, optic pallor, and reduced rod
Rod cell
Rod cells, or rods, are photoreceptor cells in the retina of the eye that can function in less intense light than can the other type of visual photoreceptor, cone cells. Named for their cylindrical shape, rods are concentrated at the outer edges of the retina and are used in peripheral vision. On...
function on electroretinography
Electroretinography
Electroretinography measures the electrical responses of various cell types in the retina, including the photoreceptors , inner retinal cells , and the ganglion cells. Electrodes are usually placed on the cornea and the skin near the eye, although it is possible to record the ERG from skin electrodes...
.
Three subtypes of CDG I (a,b,d) can cause congenital hyperinsulinism
Congenital hyperinsulinism
Congenital hyperinsulinism is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion. Congenital forms of hyperinsulinemic hypoglycemia can be transient or persistent, mild or severe. These conditions are present at birth and...
with hyperinsulinemic hypoglycemia
Hyperinsulinemic hypoglycemia
Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.-Causes:...
in infancy.
Glycosylation and known defects
A biologically very important group of carbohydrates is the asparagineAsparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
(Asn
ASN
ASN may refer to:Organisations:* ASN Bank in the Netherlands* American Society of Nephrology* American Society for Neurochemistry* American Society of Neuroimaging* American Society for Nutrition...
)-linked, or N-linked, oligosaccharide
Oligosaccharide
An oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...
s. Their biosynthetic pathway is very complex and involves a hundred or more glycosyltransferase
Glycosyltransferase
Glycosyltransferases are enzymes that act as a catalyst for the transfer of a monosaccharide unit from an activated nucleotide sugar to a glycosyl acceptor molecule, usually an alcohol....
s, glycosidases, transporter
Transporter
Transporter may refer to:* Transporter , types of vehicles designed to transport items* Volkswagen Transporter, a model of van- Film and television :...
s and synthase
Synthase
In biochemistry, a synthase is an enzyme that catalyses a synthesis process.Following the EC number classification, they belong to the group of ligases, with lyases catalysing the reverse reaction....
s. This plethora allows for the formation of a multitude of different final oligosaccharide structures, involved in protein folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
, intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
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 glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s. Lack thereof leads to leukocytosis and increase sensitivity to infections as seen in SLC35C1-CDG(CDG-IIc); caused by a GDP-fucose (Fuc) transporter deficiency.
All N-linked oligosaccharides originate from a common lipid-linked oligosaccharide (LLO) precursor, synthesized in the ER
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
on a dolichol-phosphate (Dol-P) anchor. The mature LLO is transferred co-translationally to consensus sequence Asn
ASN
ASN may refer to:Organisations:* ASN Bank in the Netherlands* American Society of Nephrology* American Society for Neurochemistry* American Society of Neuroimaging* American Society for Nutrition...
residues in the nascent protein, and is further modified by trimming and re-building in the Golgi
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
.
Deficiencies in the genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
involved in N-linked glycosylation
N-linked glycosylation
N-linked glycosylation is important for the folding of some eukaryotic proteins. The N-linked glycosylation process occurs in eukaryotes and widely in archaea, but very rarely in bacteria....
constitute the molecular background to most of the CDGs.
- Type I defects involve the synthesis and transfer of the LLO
- Type II defects impair the modification process of protein-bound oligosaccharides.
Type I
| Description | Disorder | Product |
|---|---|---|
| The formation of the LLO is initiated by the synthesis of the polyisoprenyl dolichol Dolichol Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol functional group.-Functions:... from farnesyl, a precursor Precursor (chemistry) In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway.... of cholesterol Cholesterol Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes... biosynthesis. |
A recently published paper elegantly shows how an intermediary reductase Reductase -Examples:* 5-alpha reductase* Dihydrofolate reductase* HMG-CoA reductase* Methemoglobin reductase* Ribonucleotide reductase* Thioredoxin reductase* E. coli nitroreductase* Methylenetetrahydrofolate reductase... in this process, is deficient in a Type I CDG (SRD5A3 SRD5A3 Steroid 5-alpha-reductase 3, also known as 3-oxo-5-alpha-steroid 4-dehydrogenase 3, is an enzyme that in humans is encoded by the SRD5A3 gene.... -CDG). |
 |
| Dol is then activated to Dol-P via the action of Dol kinase in the ER membrane. | This process is defective in DK1 Dolichol kinase In enzymology, a dolichol kinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are CTP and dolichol, whereas its two products are CDP and dolichyl phosphate.... -CDG (CDG-Im). |
|
| Consecutive N-acetylglucosamine N-Acetylglucosamine N-Acetylglucosamine is a monosaccharide derivative of glucose. It is an amide between glucosamine and acetic acid... (GlcNAc)- and mannosyltransferase Mannosyltransferase A mannosyltransferase is a type of glycosyltransferase that acts upon mannose.An example is heteroglycan alpha-mannosyltransferase.... s use the nucleotide Nucleotide Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions... sugar donors UDP-GlcNAc and GDP-mannose (Man) to form a pyrophosphate Pyrophosphate In chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Any salt or ester containing two phosphate groups is called a diphosphate. As a food additive, diphosphates are known as E450.- Chemistry :... -linked seven sugar glycan structure (Man5GlcNAc2-PP-Dol) on the cytoplasmatic side of the ER Endoplasmic reticulum The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae... . |
Some of these steps have been found deficient in patients.
|
Man5GlcNAc2-PP-Dol |
| The M5GlcNAc2-structure is then flipped to the ER Endoplasmic reticulum The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae... lumen, via the action of a "flippase Flippase Flippases are a family of transmembrane lipid transporter enzymes located in the membrane responsible for aiding the movement of phospholipid molecules between the two leaflets that compose a cell's membrane... " |
This is deficient in RFT1 RFT1 Protein RFT1 homolog is a protein that in humans is encoded by the RFT1 gene.Defects are associated with congenital disorder of glycosylation type 1N.-External links:*... -CDG (CDG-In). |
|
| Finally, four mannosyltransferase Mannosyltransferase A mannosyltransferase is a type of glycosyltransferase that acts upon mannose.An example is heteroglycan alpha-mannosyltransferase.... s and three glucosyltransferases complete the LLO structure Glc3Man9GlcNAc2-PP-Dol using Dol-P-Man and Dol-P-glucose (Glc) as donors. |
There are four known defects:
ALG3 Dolichyl-P-Man:ManGlcNAc-PP-dolichyl mannosyltransferase is an enzyme that in humans is encoded by the ALG3 gene.-External links:*... -CDG (CDG-Id) ALG9 Alpha-1,2-mannosyltransferase ALG9 is an enzyme that in humans is encoded by the ALG9 gene.-External links:*... -CDG (CDG-IL) ALG12 Dolichyl-P-Man:ManGlcNAc-PP-dolichyl-alpha-1,6-mannosyltransferase is an enzyme that in humans is encoded by the ALG12 gene.-External links:*... -CDG (CDG-Ig) ALG6 Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase is an enzyme that in humans is encoded by the ALG6 gene.-External links:*... -CDG (CDG-Ic) ALG8 Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase is an enzyme that in humans is encoded by the ALG8 gene.-External links:*... -CDG (CDG-Ih). |
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 MPDU1 Mannose-P-dolichol utilization defect 1 protein is a protein that in humans is encoded by the MPDU1 gene.-See also:* Dolichol monophosphate mannose* Congenital disorder of glycosylation-External links:*... -CDG (CDG-If). |
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| 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 PMI-CDG (CDG-Ib), which is the only treatable CDG-I subtype. |  |
| Man-1-P is then formed from Man-6-P, catalyzed by phosphomannomutase Phosphomannomutase In enzymology, a phosphomannomutase is an enzyme that catalyzes the chemical reactionHence, this enzyme has one substrate, alpha-D-mannose 1-phosphate, and one product, D-mannose 6-phosphate.... (PMM), 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. | |
| Dol-P-Man is formed via the action of Dol-P-Man synthase, consisting of three subunits; DPM1 DPM1 Dolichol-phosphate mannosyltransferase is an enzyme that in humans is encoded by the DPM1 gene.-External links:*... , DPM2 DPM2 Dolichol phosphate-mannose biosynthesis regulatory protein is a protein that in humans is encoded by the DPM2 gene.- Function :Dolichol-phosphate mannose serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum . Lack of Dol-P-Man results in defective surface... , and DPM3 DPM3 dolichyl-phosphate mannosyltransferase polypeptide 3, alsoknown as DPM3, is a human gene.- Function :Dolichol-phosphate mannose serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum . Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins... . |
Mutations in DPM1 causes DPM1-CDG (CDG-Ie). No patients with mutations in DPM2 and DPM3 has been found so far. |
Type II
The mature LLO chain is next transferred to the growing protein chain, a process catalysed by the oligosaccharyl transferase (OST) complex.- Once transferred to the protein chain, the oligosaccharide is trimmed by specific glycosidases. This process is vital since the lectinLectinLectins are sugar-binding proteins that are highly specific for their sugar moieties. They play a role in biological recognition phenomena involving cells and proteins. For example, some viruses use lectins to attach themselves to the cells of the host organism during infection...
chaperones calnexinCalnexinCalnexin is a 90kDa integral protein of the endoplasmic reticulum . It consists of a large N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short , acidic cytoplasmic tail....
and calreticulinCalreticulinCalreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 is a protein that in humans is encoded by the CALR gene....
, involved in protein quality, bind to the Glc1Man9GlcNAc-structure and assure proper folding. Lack of the first glycosidase (GCS1GCS1Mannosyl-oligosaccharide glucosidase is an enzyme that in humans is encoded by the MOGS gene.GCS1 may also refer to "generative cell specific 1", also called HAP2 , a gene of lower eukaryotes which is thought to be responsible for gametes fusion ..-External links:*...
) causes CDG-IIb. - Removal of the Glc residues and the first Man residue occurs in the ER.
- The glycoprotein then travels to the GolgiGolgi apparatusThe Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
, where a multitude of different structures with different biological activities are formed. - MannosidaseMannosidaseMannosidase is an enzyme which hydrolyzes mannose.There are two types:* alpha-Mannosidase* beta-MannosidaseA deficiency is associated with mannosidosis....
I creates a Man5GlcNAc2-structure on the protein, but note that this has a different structure than the one made on LLO. - Next, a GlcNAc residue forms GlcNAc1Man5GlcNAc2, the substrate for a-mannosidase II (aManII).
- aManII then removes two Man residues, creating the substrate for GlcNAc transferase II, which adds a GlcNAc to the second Man branch. This structure serves as substrate for additional galactosylation, fucosylationFucosylationFucosylation : The process of adding fucose sugar units to a molecule. It is a type of Glycosylation.It is important clinically, especially in cancer.It is performed by fucosyltransferase enzymes....
and sialylation reactions. Additionally, substitution with more GlcNAc residues can yield tri- and tetra-antennary molecules.
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.
In addition to glycosidase I, mutations have been found:
- in MGAT2MGAT2Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the MGAT2 gene.-External links:*...
, in GlcNAc transferase II (CDG-IIa) - in SLC35C1SLC35C1GDP-fucose transporter 1 is a protein that in humans is encoded by the SLC35C1 gene.Defects can be associated with Congenital disorder of glycosylation type IIc.-External links:*...
, the GDP-Fuc transporter (CDG-IIc) - in B4GALT1B4GALT1Beta-1,4-galactosyltransferase 1 is an enzyme that in humans is encoded by the B4GALT1 gene.-External links:*...
, a galactosyltransferaseGalactosyltransferaseGalactosyltransferase is a type of glycosyltransferase which catalyzes the transfer of galactose. An example is B-N-acetylglucosaminyl-glycopeptide b-1,4-galactosyltransferase....
(CDG-IId) - in COG7COG7Conserved oligomeric Golgi complex subunit 7 is a protein that in humans is encoded by the COG7 gene.-Interactions:COG7 has been shown to interact with COG4 and COG5.-External links:*...
, the conserved oligomeric Golgi complex-7 (CDG-IIe) - in SLC35A1SLC35A1CMP-sialic acid transporter is a protein that in humans is encoded by the SLC35A1 gene.-External links:*...
, the CMP-sialic acid (NeuAc) transporter (CDG-IIf)
However, the use of >100 genes in this process, presumably means that many more defects are to be found.
Treatment
No treatment is available for most of these disorders. MannoseMannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. Mannose is a C-2 epimer of glucose. It is not part of human metabolism, but is a component of microbial cell walls, and is therefore a target of the immune system and also of antibiotics....
supplementation relieves the symptoms in PMI-CDG (CDG-Ib) for the most part, even though the hepatic fibrosis may persist. Fucose
Fucose
Fucose is a hexose deoxy sugar with the chemical formula C6H12O5. It is found on N-linked glycans on the mammalian, insect and plant cell surface, and is the fundamental sub-unit of the fucoidan polysaccharide...
supplementation has had a partial effect on some SLC35C1-CDG (CDG-IIc or LAD-II) patients.
External links
- GeneReviews/NIH/NCBI/UW entry on PMM2-CDG (CDG-Ia)Carbohydrate-Deficient Glycoprotein Syndrome, Type 1a; Congenital Disorder of Glycosylation Type 1a; Jaeken Syndrome
- OMIM entries on Carbohydrate-Deficient Glycoprotein Syndrome, Type 1a; Congenital Disorder of Glycosylation Type 1a; Jaeken Syndrome
- The CDG Family Network
- GeneReviews/NIH/NCBI/UW entry on Congenital Disorders of Glycosylation Overview