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F04b57ca351b0dc3389ebe992c Review Insights into complexity of congenital disorders of glycosylation Sandra Supraha Goreta*, Sanja Dabelic, Jerka Dumic University of Zagreb, Faculty of Pharmacy and Biochemistry, Department of Biochemistry and Molecular Biology, Zagreb, Croatia *Corresponding author: [email protected] 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 cmutations, lead to the development of rare, but severe diseases – congenital disor- ders 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 someare common for several CDG types but also for other unrelated diseases, especially neurological ones, leaving the possibility that many CDGs cases are under- or mis- diagnosed. Glycan analysis of serum transferrin (by isoelectric focusing or more sophisticated methods, such as HPLC (high-performance liquid chro- matography) 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. Key words: congenital disorders of glycosylation; CDG; diagnostics; therapy Received: November 24, 2011 Accepted: March 12, 2012 Introduction Glycans (i.e. carbohydrates or sugars) can be cova- depending on the specifi c type of glycosylation. lently linked to the proteins or lipids in the process Depending on the linkage type, through which called glycosylation, thus forming diff erent types glycans are bound to the protein part, there are of glycoconjugates (glycoproteins, glycolipids, gly- two kinds of protein glycosylaton: N- and O-glyco- cosylphosphatidylinositol (GPI) anchors or proteo- sylation. The fi rst steps of N-glycosylation process glycans). The glycan parts of glycoconjugates con- involve assembling of a lipid-linked oligosaccha- tribute to diverse physical, biochemical and bio- ride (LLO) precursor. That process starts at the cy- logical properties of glycoconjugates, ranging toplasmic side of the ER and continues on the lu- from the resistance to protease degradation and minal side of the ER after the fl ipping of the grow- localization in the cell, to the regulation of immune ing precursor across the membrane bilayer by the response and metastasis spreading (1-3). Therefore mechanism which is not yet fully understood. The it is not surprising that changes of glycosylation transfer of completed LLO precursor onto amino- are related to many medical problems. Glycosyla- group of asparagine residue in Asn-X-Ser/Thr se- tion of both proteins and lipids occurs in endoplas- quon of the nascently translated polypeptide is mic reticulum (ER) and/or Golgi apparatus (GA), catalyzed by oligosaccharyltransferase. Addition- Biochemia Medica 2012;22(2):156-70 156 Supraha Goreta S. et al. Insights into complexity of CDGs al remodeling of the glycans by assembly and pro- toms highly vary, but some are common for sever- cessing reactions catalyzed by numerous glycosyl- al CDG types, such as psychomotor retardation, transferases and glycosidases continues in the lu- failure to thrive, coagulopathies, dysmorphic fea- men of ER and GA (4). O-glycosylation, attachment tures, seizures and stroke-like episodes (9,10). Clini- of glycans to the hydroxyl group of threonine or cal manifestation of CDGs ranges from very mild serine moieties of the proteins, does not comprise to extremely severe (literately, all organs can be af- processing, only assembly, which mainly occurs in fected). The resemblance to some other diseases, the Golgi apparatus. Diverse and complex glycan especially neurological ones and the physicians’ structures of glycoconjugates are therefore the unawareness of the existence of these diseases, outcome of the coordinated reactions of glycosyl- are the main reasons why CDGs still remain under- transferases, glycosidases, nucleotide-sugar-spe- or misdiagnosed. In addition, the population stud- cifi c transporters, altogether, more than 250 gene ies on the frequency of the mutations causing products. Gene mutations can cause defects of CDGs are still scarce. Based on the determined fre- these proteins resulting in inborn errors of metab- quency of heterozygotes, the estimated incidence olism, characterized by defi cient or reduced glyco- of homozygotes for certain mutations are as high sylation and known as congenital disorders of gly- as 1:20,000, suggesting the existence of much cosylation (CDGs). higher number of cases than documented (10). In this review, we will provide an overview of the Congenital disorders of glycosylation characteristics of currently known CDGs, classifi ed according to novel nomenclature (8) (with the old Since 1980, when the fi rst N-glycosylation defect one given in italics in brackets), as well as biochem- was described and characterized (5) over 45 types ical and genetic diagnostic methods and thera- of CDGs have been recognized. Although very peutic approaches for the treatment of these rare rare, CDGs are the most rapidly expanding group diseases. Due to the space limitation, this review among the currently known 3000 monogenetic describes only CDGs’ types present in more than inherited diseases. All known CDGs have a reces- few patients or characterized by unique pheno- sive inheritance except EXT1/EXT2-CDG which is type. dominantly inherited and MGAT1-CDG which is X- linked (6). Defects of protein N-glycosylation CDGs were fi rst classifi ed as type I (CDG-I) related to the disrupted synthesis of the lipid-linked oligo- Sixteen defects of protein N-glycosylation have saccharide precursor and type II (CDG-II) involving been detected so far: 14 assembly defects and 2 malfunctioning processing/assembly of the pro- processing defects, classifi ed according to the old tein-bound oligosaccharide chain (7). However, nomenclature as CDG type I (CDG-I) and CDG type since 2009, most of the researchers use a novel no- II (CDG-II), respectively. menclature based on the name of the aff ected gene (e.g. CDG-Ia = PMM2-CDG, CDG-Ib = MPI- PMM2-CDG (CDG-Ia) CDG) (8). According to the novel classifi cation, PMM2 gene (NG-009209.1), mapped on chromo- CDGs are divided into 4 categories as defects of: some 16p13, encodes phosphomannomutase (NP- • protein N-glycosylation (16 types of CDGs), 000294.1), an enzyme that transforms mannose-6- • protein O-glycosylation (8 types of CDGs), phosphate into mannose-1-phosphate (Figure 1) • lipid glycosylation and glycosylphosphatidylinosi- (11). Some of the mutations in PMM2 gene cause tol anchor glycosylation (3 types of CDGs), and PMM2-CDG (CDG-Ia, OMIM≠212065), the most prevalent type of CDGs detected in more than 700 • defects in multiple glycosylation pathways and patients worldwide (12). Molecular analysis re- in other pathways (17 types of CDGs) (6). vealed a large number (> 100) of mutations all over In addition, several CDGs of so far unknown etiol- 8 PMM2 exons, but the mutational hot spots were ogy (CDG-x) have been recognized. CDG symp- detected in exons 5 and 8 (13,14). The most fre- Biochemia Medica 2012;22(2):156-70 157 Supraha Goreta S. et al. Insights into complexity of CDGs quent mutations known by now, p.R141H and p. Clinical presentation of this disease is unique F119L, both caused by a single base mutation, among CDGs due to the fact that neurological c.422G>A (rs28936415) and c.357C>A (rs80338701), symptoms are usually absent. Gastrointestinal respectively (15), are located in exon 5. p.R141H has tract and the liver are mainly aff ected and symp- never been observed in the homozygous form, toms usually comprise vomiting, diarrhea, gastro- thus being considered lethal (15). Interestingly, intestinal bleeding, protein-losing enteropathy PMM2-CDG patients (heterozygotes for p.R141H) and hepatomegaly. Additionally, in more severe have 0-10% of normal PMM2 activity in fi broblasts cases, hypoglycemia, coagulopathy, as well as and leukocytes while their asymptomatic parents, thrombotic events (protein C and S defi ciency, low who are also heterozygotes have approximately antithrombin III levels) can be observed. Interest- 50% residual activity of PMM2 enzyme. It seems ingly, MPI-CDG is one of a few CDGs which can be that compound heterozygosity for p.R141H and eff ectively treated by oral administration of man- some other mutations in PMM2 gene (e.g. p.F119L) nose. Since it is potentially lethal, it is of utmost im- is responsible for the decreased PMM2 activity, in- portance to examine patients with inexplicable adequate for normal glycosylation. Mutation
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