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Congenital disorders of glycosylation (CDG) represent a constellation of diseases that result from defects in the synthesis of carbohydrate structures (glycans) and in the attachment of glycans to other compounds. These defective processes involve the N-linked and O-linked glycosylation pathways, GPI-linkage, biosynthesis of proteoglycans as well as lipid glycosylation pathways. Given the range of disorders that result from CDG this page will focus primarily on the CDG that encompass defects in N-glycosylation of proteins. There are also syndromes related to defects in O-glycosylation and they are briefly mentioned at the end of this discussion.
To date at least 25 CDG have been identified with 16 of these disorders involving defective N-gycosylation of proteins. The CDG encompassing N-glycosylation defects are clustered into two broad categories. Group I CDG diseases are defined by alterations/deficiencies in the synthesis and/or transfer of the Dol-PP-oligosaccharide precursor to Asn residues in substrate proteins. Group II CDG diseases are defined as those that result from defects in subsequent N-linked glycan processing.
Abbreviations used in the following descriptions include: Dol = dolichol; Fuc = fucose; Gal = galactose; Glc = glucose; GlcNAc = N-acetylglucosamine; Man = mannose; P = phosphate
CDG-Ia is the most commonly occurring CDG, with appearance in individuals of European ancestry being highest. CDG-Ia results from mutations in phosphomannomutase 2 (gene symbol = PMM2) the enzyme that is required to convert Man-6-P to Man-1-P used in the generation of GDP-Man. Over 60 mutations in PMM2 have been identified that either decrease enzyme activity or stability.
The PMM2 gene is located on chromosome 16p13.3-p13.2 and is composed of 8 exons that encode a 246 amino acid protein.
Although there is considerable variability in the clinical phenotypes observed in CDG-Ia patients, there is always some level of psychomotor retardation and is most cases it is quite profound. In addition, infants are ataxic, exhibit axial hypotonia, and have skeletal abnormalities consisting of long limbs and short torsos. Infants manifest with feeding problems that include vomiting, anorexia, and diarrhea. Other classical hallmarks of CDG-Ia are cerebellar hypoplasia and strabismus (lack of coordinated eye movements). Due to defective synthesis of coagulation factors by the liver (primarily factor XI, antithrombin III, protein C and protein S), patients have severe coagulation defects. Adding to the situation is hepatomegaly with consequent liver dysfunction. About 20% of all CDG-Ia patients will die within the first year of life. However, most adults with the disorder have pleasant personalities even in the presence of stable mental retardation and variable peripheral neuropathy.
CDG-Ib results from defects in phosphomannose isomerase (gene symbol = MPI) necessary to convert fructose-6-P to Man-6-P. This enzyme carries out its function just prior to the role of PMM2 described for CDG-Ia. Deficiencies in MPI cause loss of plasma proteins via the intestines (protein-losing enteropathy, PLE), diarrhea and cyclical vomiting. Liver dysfunction is caused by hepatomegaly and results in coagulation defects and hypoglycemia. Thankfully, CDG-Ib patients are spared from mental defects. One explanation for the lack of demonstrable neurologic deficit in CDG-Ib compared to CDG-Ia is that brain hexokinase can phosphorylate mannose to Man-6-P thereby, bypassing the need for PMI. However, liver glucokinase does not phosphorylate mannose thus, there are the associated hepatic anomalies with CDG-Ib. Because free mannose is not found at any appreciable level in foods, dietary supplementation with mannose can ameliorate some of the symptoms of CDG-Ib.
The MPI gene is located on chromosome 15q22-qter and is composed of 8 exons spanning 5kbp encoding a 423 amino acid protein.
CDG-Ic results from defects in glucosyltransferase I (Dol-P-Glc: Man9-GlcNAc2-P-P-Dol glucosyltransferase; gene symbol = ALG6 which refers to asparagine-linked glycosylation gene 6) and eight mutations have been identified in the gene in patients with this disorder. ALG6 catalyzes the addition of the first glucose residue to the en bloc oligosaccharide that is subsequently N-linked to proteins. As a consequence of the defective ALG6 enzyme, the oligosaccharide unit is not transferred from dolichol to proteins. Symptoms of CDG-Ic are similar to those of CDG-Ia but much less severe. Patients have frequent seizures, psychomotor retardation that is milder than in CDG-Ia, pronounced axial hypotonia, and strabismus. Intestinal symptoms of CDG-Ic are markedly exacerbated by intestinal viral infections due to a decline of glycosylated structures (both proteins and proteoglycans) on the basolateral surfaces of intestinal enterocytes.
The ALG6 gene is located on chromosome 1p22.3 and is composed of 14 exons spanning 55kbp encoding a 507 amino acid transmembrane protein.
Few cases of CDG-Id, CDG-Ie and CDG-If have been reported in the literature. Each of these three disorders are related via enzymes that synthesize or utilize Dol-P-Man structures.
CDG-Id results from deficiencies in mannosyltransferase VI (Dol-P-Man: Man5GlcNAc2-P-P-Dol mannosyltransferase; gene symbol = ALG3). This enzyme transfers Man from Dol-P-Man to Dol-PP-Man5GlcNAc2 of the growing en bloc oligosaccharide. CDG-Id individuals suffer severe neurological impairment including profound psychomotor retardation and intractable seizures, eye abnormalities, optic atrophy, postnatal microcephaly, and hypsarrhythmia (abnormal EKG patterns observed in infants suffering spasms).
The ALG3 gene is located on chromosome 3q27 encoding a 438 amino acid protein.
CDG-Ie results from defects in the catalytic subunit of Dol-P-Man synthase I (GDP-Man: Dol-P mannosyltransferase 1; gene symbol = DPM1). Dol-P-Man synthase I is an enzyme complex composed of at least three subunits identified as DPM1, DPM2, and DPM3. The catalytic subunit (DPM1) is stabilized via its association with the C-terminal domain of the DPM3 subunit and this interaction is stabilized by the DPM2 subunit. Dol-P-Man is required for mannose elongation reactions necessary to produce the en bloc oligosaccharide of N-glycans, GPI-anchored proteins and many other Man-containing glycoconjugates. Like patients with CDG-Id, CDG-Ie infants suffer severe neurological impairment including profound psychomotor retardation, intractable seizures, hypotonia, eye abnormalities, cortical blindness, and failure to thrive.
The DPM1 gene is located on chromosome 20q13.13.
CDG-If results from defects in the protein responsible for utilization of Dol-P-Man independent of DPM1 which is defective in CDG-Ie. The gene encoding this activity is identified as Man-P-Dol utilization defect 1 (gene symbol = MPDU1) and it is required for the utilization of Dol-P-Man and Dol-P-Glc. The MPDU1 gene was identified on the basis of the fact that it could rescue defects in Chinese hamster ovary (CHO) cells that prevented the synthesis and utilization of Dol-P-Man. The CHO cell mutations were identified as Lec15 and Lec35 (synthesis and utilization, respectively) and the rescue gene was called SL15 for suppressor of Lec15. This gene was shown to rescue both the Lec15 and Lec35 defects.
Persons with CDG-If have clinical symptoms including dwarfism, hypotonia, frequent seizures, severe psychomotor retardation and cerebral atrophy. Additionally, these individuals have severe failure to thrive after birth.
The MPDU1 gene is located on chromosome 17p13.1-p12 encoding a 247 amino acid transmembrane protein. Both the N-terminus and C-terminus of the MPDU1 protein are localized to the cytoplasm.
CDG-Ig results from deficiencies in mannosyltransferase VIII (Dol-P-Man: Man7-GlcNAc2-P-P-Dol α-6-mannosyltransferase; gene symbol = ALG12). The common clinical features associated with CDG-Ig are pschomotor retardation, facial dysmorphy, and hypotonia. In some patients there are feeding problems, microcephaly, convulsions, and frequent respiratory tract infections.
CDG-Ih results from deficiencies in glucosyltransferase II (Dol-P-Glc: Glc1-Man9-GlcNAc2-P-P-Dol α-3-glucosyltransferase; gene symbol = ALG8). To date five children have been identified with CDG-Ih. Their symptoms included moderate hepatomegaly, PLE (see CDG-Ib), hypotonia, lung hypoplasia, anemia, and thrombocytopenia. All but one of the observed patients succumbed the the disorder within the first year of life.
CDG-Ii results from deficiencies in mannosyltransferase II (GDP-Man: Man1-GlcNAc2-P-P-Dol mannosyltransferase; gene symbol = ALG2). The single patient thus far identified with this form of CDG exhibited severe psychomotor retardation, spasms, hypsarrhythmia, and irregular nystagmus (involuntary eye movements). Examination of the brain by MRI showed significant dysmyelination.
CDG-Ij results from deficiencies in UDP-GlcNAc: Dol-P-GlcNAc-P phosphotransferase (gene symbol = DPAGT1). A single patient has been described with this form of CDG. The infant suffered from intractable spasms, was hyoptonic and had sever psychomotor retardation. Dysmorphy was noted with microcephaly, micrognathia (undersized jaw), and estropia (a form of strabismus where one or both eyes turn inward).
CDG-Ik results from deficiencies in mannosyltransferase I (GDP-Man: GlcNAc2-P-P-Dol β-1,4-mannosyltransferase; gene symbol = ALG1). Each of the infants that were identified with this form of CDG exhibited seizures, severe psychomotor retardation, and early death. Variable symptoms in the patients included hypotonia, dysmorphy, microcephaly, liver dysfunction, severe infections, and coagulation defects.
CDG-IL results from deficiencies in mannosyltransferase VII-IX (Dol-P-Man: Man6- and Man8-GlcNAc2-P-P-Dol mannosyltransferase; gene symbol = ALG9). Two patients with CDG-IL have been identified. Both exhibited psychomotor retardation, hypotonia, hepatomegaly, microcephaly, and seizures.
CDG-IIa results from loss of the enzyme UDP-N-acetylglucosamine:α-6-D-mannoside-β-1,2-N-acetylglucosaminyltransferase II (GlcNAc-TII) which is encoded by the MGAT2 gene. The results of this defect are significant loss of complex sialylated structures. Following transfer of the en bloc oligosaccharide to N residues, only monosialylated structures are made. Symptoms of CDG-IIa include severe psychomotor retardation, hypotonia, coarse facies and frequent infections. In experiments in mice it was found that MGAT2 null animals all died within 4 weeks after birth and a significant number die in utero from gastrointestinal blockage. From these results it is speculated that the true incidence of human MGAT2 defects may go undetected due to spontaneous fetal abortion or death shortly after birth.
CDG-IIb results from deficiencies in glucosidase I (gene symbol = GLS1). A single patient identified with CDG-IIb exhibited dysmorphic features, seizures, hypotonia, hepatomegaly, feeding difficulty, and failure to thrive. This patient did not survive.
CDG-IIc is more commonly referred to as leukocyte adhesion deficiency syndrome II (LAD II). LAD II belongs to the class of disorders referred to as primary immunodeficiency syndromes as the symptoms of the disease manifest due to defects in leukocyte function. Symptoms of LAD II are characterized by unique facial features, recurrent infections, persistent leukocytosis, defective neutrophil chemotaxis and severe growth and mental retardation. The genetic defect resulting in LAD II is in the pathway of fucose utilization leading to loss of fucosylated glycans on the cell surface. An additional feature of LAD II is that individuals harbor the rare Bombay (hh) blood type at the ABO locus as well as lack the Lewis blood group antigens. The Bombay blood type is characterized by a deficiency in the H (referred to as the O-type), A and B antigens due to loss of the fucose residue. Each of these blood group antigens contains a Fuc-α-1,2-Gal modification that is the final carbohydrate addition to these antigens. These fucosylation reactions are catalyzed by α-1,2-fucosyltransferase which is encoded by the H and Se loci. The defective neutrophil chemotaxis is due to the loss of a selectin ligand on these cells. This ligand is the sialylated Lewisx antigen, another blood group antigen.
The recurrent infections seen in LAD II patients are the result of the defective neutrophil function. Neutrophils are involved in innate immunity responses to bacterial infection. To carry out their role in host defense mechanisms, neutrophils must adhere to the surface of the endothelium at the site of inflammation which is an event mediated by cell surface adhesion molecules. The selectin family (E-, L-, and P-selectins) of animal lectins are necessary to mediate the initial process of neutrophil adherence to the endothelium. The selectins recognize sialylated fucosylated lactosamines typified by the Lewisx antigen. Once neutrophils adhere and roll along the surface of the endothelium (due to vascular flow), the integrin family of adhesion molecules allow for firm adherence followed by tissue penetration. A related disorder, termed LAD I, is caused by the absence of CD18 which is the β2 subunit of the leukocyte integrin found on the surface of neutrophils and monocytes.
Because there is widespread loss of fucosylated antigens in LAD II patients, each of which can be formed through the actions of several fucosyltransferases, the role of these enzymes in the disease could be ruled out. In addition, normal levels of the α-1,2-, α-1,3- and α-1,4-fucosyltransferases were observed in the serum of LAD II individuals. These observations indicated that the pathways to GDP-fucose synthesis or utilization by the fucosyltransferases in the Golgi must be deficient in LAD II. Fucose can be converted to GDP-fucose by salvage of free fucose (exogenous or derived through glycoconjugate degradation) or by epimerization of GDP-mannose. In order for GDP-fucose to be utilized by Golgi fucosyltransferases it must first be transported into the Golgi from the cytosol where it is synthesized. Examinations of the enzymes involved in the synthesis and transport of GDP-fucose have been undertaken. While the activity of one of the enzymes of GDP-mannose epimerization (GDP-D-mannose 4,6-dehydratase, GMD) has been shown to be reduced in LAD II patients, it has been determined that the major defect causing LAD II is an impairment in the transport of GDP-fucose into the Golgi. This latter reaction is catalyzed by the GDP-fucose transporter encoded by the FUCT1 gene (also identified as solute carrier family 35, member C1: SCL35C1).
CDG-IId results from deficiencies in β-1,4-galactosyltransferase (gene symbol = B4GALT1). Only one patient has been identified with CDG-IId. The child exhibited psychomotor retardation, severe spontaneous bleeding, hydrocephalus, and myopathy.
Protein O-glycosylation Defects:
Multiple cartilagenous exostoses (MCE) and a progeroid form (accelerated aging) of Ehlers-Danlos syndrome are the result of defects in O-xylosylation. The different forms of MCE result from defects in either the EXT1 or EXT2 genes which encode glucuronyltransferase and N-acetylglucosaminyltransferase, respectively. The EDS progeroid form is caused by a protein O-glycosylation defect is the result of deficiency in the B4GALT7 gene encoding β-1,4-galactosyltransferase 7. This gene is also identified by the name xylosylprotein 4-β-galactosyltransferase (XGALT1 or XGPT1.
Hyperphosphatemic familial tumoral calcinosis (HFTC) results from defects in O-N-acetylgalactosaminylation which is catalyzed by the GALNT3 gene encoding polypeptide N-acetylgalactosaminyltransferase 3. Additional causes of HFTC are not related to protein glycosylation but involve genes encoding participants in signal transduction by fibroblast growth factors, FGFs, specifically mutations in FGF23 and KLOTHO. FGF23 is known to interact with KLOTHO and then complex binds to its receptor which is likely to be FGF receptor 1 (FGFR1). The KLOTHO gene was originally isolated from a mouse model of age-related disorders and thus the gene was named after the Fate of Greek mythology who spins the thread of life.
There are two disorders that result from defects in O-mannosylation. These are Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). WWS results from a deficiency in either of two genes POMT1 or POMT2. These genes encode O-mannosyltransferase-1 and -2, respectively. MEB is caused by deficiency in the POMGNT1 gene which encodes O-mannose β-1,2-N-acetylglucosaminyltransferase.
Spondylocostal dysotosis type 3 results from a defect in O-fucosylation. The reaction is catalyzed by O-fucose-specific β-1,3-N-acetylglucosaminyltransferase encoded by the SCD03 gene. This gene is more commonly known as lunatic fringe (LFNG). The lunatic fringe protein is the human homolog of the fruit fly gene fringe which was identified as a mutation resulting in defective early development. Lunatic fringe modulates the activation of the Notch receptor signal transduction pathway. Lunatic fringe incorporates O-fucose residues into the epidermal growth factor-like (EGF-like) repeats of Notch receptors.
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