Abstract
Biochemical and biological properties of glycoconjugates are strongly determined by the specific structure of its glycan parts. Glycosylation, the covalent attachment of sugars to proteins and lipids, is very complex and highly-coordinated process involving > 250 gene products. Deficiency of glycosylation enzymes or transporters results in impaired glycosylation, and consequently pathological modulation of many physiological processes. Inborn defects of glycosylation enzymes, caused by the specific mutations, lead to the development of rare, but severe diseases - congenital disorders of glycosylation (CDGs). Up today, there are more than 45 known CDGs. Their clinical manifestations range from very mild to extremely severe (even lethal) and unfortunately, only three of them can be effectively treated nowadays. CDG symptoms highly vary, though some are common for several CDG types but also for other unrelated diseases, especially neurological ones, leaving the possibility that many CDGs cases are under- or misdiagnosed. Glycan analysis of serum transferrin (by isoelectric focusing or more sophisticated methods, such as HPLC (high-performance liquid chromatography) or MALDI (matrix-assisted laser desorption/ionization)) or serum N-glycans (by MS), enzyme activity assays and DNA sequence analysis are the most frequently used methods for CDG screening and identification, since no specific tests are available yet. In this review we summarize the current knowledge on the clinical, biochemical and genetic characteristic of distinct CDGs, as well as existing diagnostic and therapeutic procedures, aiming to contribute to the awareness on the existence of these rare diseases and encourage the efforts to elucidate its genetic background, improve diagnostics and develop new strategies for their treatment.
Highlights
Glycans can be covalently linked to the proteins or lipids in the process called glycosylation, forming different types of glycoconjugates (glycoproteins, glycolipids, glycosylphosphatidylinositol (GPI) anchors or proteoglycans)
Laboratory findings of type 2 pattern on transferrin isoelectrofocusing (Tf-isoelectric focusing (IEF)), abnormal isoelectrofocusing of apolipoprotein C-III, and abnormal mass spectrometry of glycans of total serum proteins could be ascribed to the classical congenital disorders of glycosylation (CDGs) type II caused by defects of enzymes involved in glycan processing [50,51], the cause of glycosylation disturbance lies in defects of α-subunit of the vesicular ATPase H+pump
Many glycosylation pathways are not yet elucidated and numerous glycan roles wait to be identified. 250 gene products are recognized to be involved in glycosylation pathways, it is reasonable to believe that in addition to 45 recognized CDGs many others will be discovered
Summary
Glycans (i.e. carbohydrates or sugars) can be covalently linked to the proteins or lipids in the process called glycosylation, forming different types of glycoconjugates (glycoproteins, glycolipids, glycosylphosphatidylinositol (GPI) anchors or proteoglycans). It is not surprising that changes of glycosylation are related to many medical problems Glycosylation of both proteins and lipids occurs in endoplasmic reticulum (ER) and/or Golgi apparatus (GA), depending on the specific type of glycosylation. The first steps of N-glycosylation process involve assembling of a lipid-linked oligosaccharide (LLO) precursor. Insights into complexity of CDGs al remodeling of the glycans by assembly and processing reactions catalyzed by numerous glycosyltransferases and glycosidases continues in the lumen of ER and GA [4]. Diverse and complex glycan structures of glycoconjugates are the outcome of the coordinated reactions of glycosyltransferases, glycosidases, nucleotide-sugar-specific transporters, altogether, more than 250 gene products. Gene mutations can cause defects of these proteins resulting in inborn errors of metabolism, characterized by deficient or reduced glycosylation and known as congenital disorders of glycosylation (CDGs)
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