Insights into complexity of congenital disorders of glycosylation

Abstract

Biochemical and biological properties of glycoconjugates are strongly determined by the specifi c 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. Defi ciency 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 specifi c 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 eff ectively 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 identifi cation, since no specifi c 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 eff orts to elucidate its genetic background, improve diagnostics and develop new strategies for their treatment.

The Close Relationship between the Golgi Trafficking Machinery and Protein Glycosylation

“…So far, more than 100 monogenic congenital disorders of glycosylation (CDGs) have been identified and associated with a wide variety of symptoms such as neurological deficit, liver disfunction, and skin and bone alterations [ 20 , 21 ]. Traditionally CDGs have been divided into two groups: CDG-I affect the synthesis and/or transfer of the dolichol pyrophosphate oligosaccharide precursor of N -linked glycoproteins, while CDG-II affect the processing of N -linked glycans or the biosynthesis of O- linked glycans [ 22 ]. Many pathogenic mutations in intra-Golgi trafficking regulators have been associated with CDG II.…”

COG7 deficiency in Drosophila generates multifaceted developmental, behavioral and protein glycosylation phenotypes

“…Because 2% of the translated genome encodes the glycosylation machinery, many other CDGs remain to be discovered (Freeze et al, 2015). CDGs are divided into two large groups (Freeze et al, 2014;Goreta et al, 2012). Type I CDGs affect the synthesis of the dolichol-linked oligosaccharide, the major precursor of N-linked glycoproteins, and its transfer to acceptor proteins (Freeze et al, 2014).…”

“…Type I CDGs affect the synthesis of the dolichol-linked oligosaccharide, the major precursor of N-linked glycoproteins, and its transfer to acceptor proteins (Freeze et al, 2014). Type II CDGs disrupt either the processing of N-linked glycans, the biosynthesis of O-linked oligosaccharides or the addition of glycans to lipids (Freeze et al, 2014;Goreta et al, 2012). The eight-subunit Conserved Oligomeric Golgi (COG) complex is required for tethering of vesicles that recycle Golgi resident proteins and glycosylation enzymes (Climer et al, 2015;Miller and Ungar, 2012).…”

Comparison of transferrin isoform analysis by capillary electrophoresis and HPLC for screening congenital disorders of glycosylation

“…Symptoms observed are highly variable, however, a few common presenting features include hypotonia, skin manifestations, cutix laxa, coagulopathies, inverted nipples, cerebellar atrophy, and hypoplasia etc. These patients show global developmental delay (GDD) often with or without neurological involvement . These features are overlapping with several non‐genetic conditions and hence screening for CDG would assist in all unexplained conditions.…”