CDG, formerly known as carbohydrate-deficient glycoprotein syndrome, is one of several rare inborn errors of metabolism in which multiple tissue proteins or lipids are deficiently or defectively glycosylated. More than 150 CDG types have been described, which can be divided into four categories: disorders of protein N-glycosylation, disorders of protein O-glycosylation disorders, disorders of glycosphingolipid and glycosylphosphatidylinositol (GPI) glycosylation, and disorders of combined glycosylation. The current nomenclature of "affected gene name-CDG" is used, such as PMM2-CDG. Glycan Profiling and Glycan Structure Analysis enzymatic activity and metabolite determination, biochemical analysis, and molecular testing are the four methods that can be used in laboratories to detect CDG. All CDGs are associated with changes in glycosylation at least to some extent. Therefore, glycan analysis is the most promising CDG screening method.
The CDG type affecting Protein N-Glycosylation is the most common CDG. During N-glycosylation, specific types of CDGs can be triggered by the disorders of primarily N-linked Monosaccharide Synthesis and interconversion, disorders of glycan precursor, disorders of N-glycan transfer to protein, and N-glycan processing. So far, 16 protein N-glycosylation defects have been detected: 14 assembly defects and 2 processing defects.
CDGs are rare mainly because embryos with complete defects in the glycosylation step often do not survive, demonstrating the key biological role of glycans in humans. Abnormalities in the N-linked monosaccharides used to synthesize N-glycan precursors lead to corresponding glycosylation diseases. For example, the two most common types of CDGs (PMM2-CDG and MPI-CDG) are triggered by defects of phosphomannomutase (PMM2) and mannose-phosphate isomerase (MPI) in the cytoplasm. These two enzymes are involved in the synthesis of mannose-1-phosphate (Man-1-P) and Man-6-P. Here, we will introduce these two types of CDG in detail.
Fig.1 Biosynthesis of primarily N-linked monosaccharide synthesis and interconversion. (Hennet, 2012)
Man is a major carbohydrate that can be used to assemble complex N-glycans. The cytosolic enzyme PMM2 catalyzes the conversion of Man-6-P to Man-1-P. Man-1-P is a precursor for the synthesis of GDP-(Dol-P-Man) and is involved in the synthesis of lipid-bound oligosaccharide (LLO) precursor (Glc3Man9GlcNAc2-PP-Dol) of N-glycans. The most common disorder of glycosylation, PMM2-CDG, is an incurable autosomal recessive disease caused by mutations of gene PMM2 that encodes PMM2. PMM2-CDG manifests as neurologic or multisystem phenotypes such as psychomotor retardation, seizures, ataxia, visual impairment, hypotonia, and coagulopathy. Currently, more than 100 mutations in the PMM2 gene have been reported, among which the R141H is by far the most common mutation. The type of mutation in the PMM2 gene affects the severity of glycosylation disorders, which range from mild cognitive impairment when the enzyme is still partially active to embryonic lethal when the enzyme is completely inactive.
MPI is an enzyme that promotes the interconversion of fructose 6-phosphate (Fru-6-P) and Man-6-P. MPI can also be used to synthesize GDP-Man in eukaryotes. MPI-CDG is the second most common CDG, caused by mutations in the MPI gene encoding Man-6-P isomerase. Unlike PMM2-CDG, the clinical presentation of MPI-CDG lacks neurological involvement. MPI-CDG cases mainly present with diarrhea, vomiting, gastrointestinal bleeding, protein-losing enteropathy, hepatomegaly, and liver fibrosis. Since Man-6-P can also be directly produced by hexokinase-catalyzed Man phosphorylation, MPI-CDG patients can be treated with dietary monosaccharide supplementation and are well tolerated.
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