Congenital disorders of glycosylation (CDG) are a rapidly growing disease family with about 40 diseases reported since its first clinical description in 1980 [1]. The large majority of these are diseases of protein hypoglycosylation, but in recent years several defects in lipid glycosylation have also been identified [2,3]. Most protein glycosylation disorders are due to defects in the N-glycosylation pathway, the remaining ones affecting the O-glycosylation pathway or combined N-and O-glycosylation pathways. No defects in C-glycosylation have been detected yet. The first described CDG patients were shown to have an abnormal serum transferrin (Tf) isoelectrofocusing (IEF) pattern with increases in the di-and asialotransferrin fractions [4]. They were found to have deficient phosphomannomutase (PMM) activity [5] and mutations in the PMM2 gene [6]. PMM-deficient patients were designated as CDG-Ia. Subsequently, a patient was discovered with a serum Tf IEF pattern characterized by increases not only of the even (2 and 0) but also of the uneven (3 and 1) sialoTf bands [7]. Since these patterns were qualitatively different, we called the latter a type 2 pattern as opposed to the type 1 pattern seen in PMM deficiency. In the patient with the type 2 pattern, a deficiency was demonstrated to be in a Golgi glycosyltransferase, namely N-acetylglucosaminyltransferase II [8]. This disease was labeled CDG-IIa. New patients were classified as CDG-I or CDG-II according to the Tf IEF pattern, and each new defect took the next letter of the alphabet.
We presently count 14 CDG-I diseases (CDG-Ia up to CDG-In), and 8 CDG-II diseases (CDG-IIa up to CDG-IIh). Since this nomenclature is based on the Tf IEF pattern, it relates only to N-glycosylation diseases associated with deficient sialylation. Gradually it became clear that CDG-I defects were limited to defects in pre-ER or ER proteins whereas CDG-II defects were caused by defects in Golgi or Golgi-associated proteins. However, some of these disorders also show abnormal O-glycosylation such as the COG defects (review in [9]) and the V-ATPase defect in cutis laxa type II [10]. Also, it appeared that a patient with an alpha-glucosidase I deficiency in the ER had a normal Tf IEF pattern [11]. Still this patient was labeled as CDG-IIb, which is an inconsistency of this classification. For this reason and for a number of other reasons explained elsewhere [12], we strongly suggest that this nomenclature should be discontinued in favor of a transparent designation of glycosylation disorders and that it be applied to new and established types of CDG. We propose using only the official gene symbol (not in italics) followed by ‘-CDG’ (list of approved gene names at http://www.genenames.org). A classification of the known types of CDG, along with the traditional and new nomenclature, is shown in Table 1 (adapted from [12]).
Table 1.
Proposed nomenclature for CDG (nomenclature to be superseded is included in italics and enclosed in parenthesis).a
| Disease name | Defective protein | OMIM |
|---|---|---|
| A. Defects in protein N-glycosylation | ||
| PMM2-CDG (CDG-Ia) | Phosphomannomutase 2 | 601785 |
| MPI -CDG (CDG-Ib) | Phosphomannose isomerase | 602579 |
| ALG6-CDG (CDG-Ic) | Dol-P-Glc: Man9-GlcNAc2-P-P-Dol glucosyltransferase (glucosyltransferase 1) | 603147 |
| ALG3-CDG (CDG-Id) | Dol-P-Man: Man5-GlcNAc2-P-P-Dol mannosyltransferase (mannosyltransferase 6) | 601110 |
| ALG12-CDG (CDG-Ig) | Dol-P-Man: Man7-GlcNAc2-P-P-Dol mannosyltransferase (mannosyltransferase 8) | 607143 |
| ALG8-CDG (CDG-Ih) | Dol-P-Glc: Glc1-Man9-GlcNAc2-P-P-Dol glucosyltransferase (glucosyltransferase 2) | 608104 |
| ALG2-CDG (CDG-Ii) | GDP-Man: Man1-GlcNAc2-P-P-Dol mannosyltransferase (mannosyltransferase 2) | 607906 |
| DPAGT1-CDG (CDG Ij) | UDP-GlcNAc: Dol-P-GlcNAc-P transferase | 608093 |
| ALG1-CDG (CDG-Ik) | GDP-Man: GlcNAc2-P-P-Dol mannosyltransferase (mannosyltransferase 1) | 608540 |
| ALG9-CDG (CDG-Il) | Dol-P-Man: Man6-and Man8-GlcNA2-P-P-Dol mannosyltransferase (mannosyltransferase 7-9) | 608776 |
| RFT1-CDG (CDG-In) | Flippase of Man5GlcNAc2-PP-Dol | 611633 |
| MGAT2-CDG (CDG-IIa) | N-acetylglucosaminyltransferase 2 | 602616 |
| GCS1-CDG (CDG-IIb) | Glucosidase 1 | 606056 |
| TUSC3-CDG | Oligosaccharyltransferase subunit | 601385 |
| MGAT1-CDG | Oligosaccharyltransferase subunit | 300716 |
| B. Defects in protein O-glycosylation | ||
| *O-xylosylglycan synthesis | ||
| • EXT1/EXT2-CDG (multiple cartilaginous exostoses) | Glucuronyltransferase/N-acetylglucosaminyltransferase | 608177/608210 |
| • B4GALT7-CDG | β-1, 4-galactosyltransferase 7 | 604327 |
| *O-N-acetylgalactosaminylglycan synthesis | ||
| •GALNT3-CDG (familial tumoral calcinosis) | Polypeptide N-acetylgalactosaminyltransferase 3 | 601756 |
| *O-xylosyl/N-acetylgalactosaminylglycan synthesis | ||
| •SLC35D1-CDG (Schneckenbecken dysplasia) | Solute carrier family 35 (UDP-glucuronic acid/UDP-N-acetylgalactosamine dual transporter), member D1 | 610804 |
| *O-mannosylglycan synthesis | ||
| •POMT1/POMT2-CDG (cong. Muscular dystrophy spectrum) | O-mannosyltransferase 1 | 607423 |
| •POMGNT1-CDG (cong. Muscular dystrophy spectrum) | O-mannose β-1, 2-N-acetylglucosaminyltransferase | 606822 |
| •FKTN-CDG (cong. muscular dystrophy spectrum) | Fukutin | 607440 |
| •FKRP-CDG (cong. muscular dystrophy spectrum) | Fukutin-related protein | 606596 |
| •LARGE-CDG (cong. muscular dystrophy spectrum) | N-acetylglucosaminyltransferase-like protein | 603590 |
| *O-fucosylglycan synthesis | ||
| •LFNG-CDG (spondylocostal dysostosis type 3) | O-fucose-specific β-1, 3-N-acetylglucosaminyltransferase | 602576 |
| •B3GALTL-CDG (Peters plus syndrome) | O-fucose-specific β-1, 3-glucosyltransferase | 610308 |
| C. Defects in glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation | ||
| ST3GAL5-CDG (Amish infantile epilepsy) | Lactosylceramide α-2, 3 sialyltransferase (GM3 synthase) | 609056 |
| PIGM-CDG (glycosylphosphatidylinositol deficiency) | Phosphatidylinositolglycan, class M | 610273 |
| D. Defects in multiple glycosylation and other pathways | ||
| DPM1-CDG (CDG-Ie) | GDP-Man: Dol-P-mannosyltransferase (Dol-P-Man synthase 1) | 603503 |
| MPDU1-CDG (CDG-If) | Lec35 (Man-P-Dol utilization 1) | 608799 |
| B4GALT1-CDG (CDG-IId) | β-1, 4-galactosyltransferase 1 | 607091 |
| GNE-CDG (hereditary inclusion body myopathy) | UDP-GlcNAc epimerase/kinase | 600737 |
| SLC35A1-CDG (CDG-IIf) (CMP-sialic acid transporter deficiency) | CMP-sialic acid transporter | 605634 |
| SLC35C1-CDG (CDG-IIc) (GDP-fucose transporter deficiency) | GDP-fucose transporter | 605881 |
| *Dolichol pathway -DK1-CDG (CDG-Im) | Dolichol kinase | 610768 |
| *COGb complex | ||
| •COG7-CDG (CDG-IIe) | Component of conserved oligomeric Golgi complex 7 | 606978 |
| •COG1-CDG (CDG-IIg) | Component of conserved oligomeric Golgi complex 1 | 606973 |
| •COG8-CDG | Component of conserved oligomeric Golgi complex 8 | 606979 |
| •COG4-CDG | Component of conserved oligomeric Golgi complex 4 | 606976 |
| •COG5-CDG | Component of conserved oligomeric Golgi complex 5 | 606821 |
| *V-ATPase | ||
| •ATP6VOA2-CDG (cutis laxa type II) | V0 subunit A2 of vesicular H(+)-ATPase | 611716 |
| •SEC23B-CDG (CDAII) | COPII component SEC23B | 610512 |
Adapted from [12].
Conserved oligomeric Golgi.
References
- 1.Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P, et al. Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG deficiency, increased serum arylsulfatase A and increased CSF protein: a new syndrome. Pediatr Res. 1980;14:179. [Google Scholar]
- 2.Freeze HH. Genetic defects in the human glycome. Nat Rev Genet. 2006;7:537–551. doi: 10.1038/nrg1894. [DOI] [PubMed] [Google Scholar]
- 3.Jaeken J, Matthijs G. Congenital disorders of glycosylation: a rapidly expanding disease family. Annu Rev Genomics Hum Genet. 2007;8:261–278. doi: 10.1146/annurev.genom.8.080706.092327. [DOI] [PubMed] [Google Scholar]
- 4.Jaeken J, van Eijk HG, van der Heul C, Corbeel L, Eeckels R, Eggermont E. Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome. Clin Chim Acta. 1984;144:245–247. doi: 10.1016/0009-8981(84)90059-7. [DOI] [PubMed] [Google Scholar]
- 5.Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett. 1995;377:318–320. doi: 10.1016/0014-5793(95)01357-1. [DOI] [PubMed] [Google Scholar]
- 6.Matthijs G, Schollen E, Pardon E, et al. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome) Nat Genet. 1997;16:88–92. doi: 10.1038/ng0597-88. Erratum in Nat Genet 1997; 16: 316. [DOI] [PubMed] [Google Scholar]
- 7.Ramaekers VT, Stibler H, Kint J, Jaeken J. A new variant of the carbohydrate deficient glycoproteins syndrome. J Inherit Metab Dis. 1991;14:385–388. doi: 10.1007/BF01811710. [DOI] [PubMed] [Google Scholar]
- 8.Jaeken J, Schachter H, Carchon H, De Cock P, Coddeville B, Spik G. Carbohydrate deficient glycoprotein syndrome type II: a deficiency in Golgi localised Nacetylglucosaminyltransferase II. Arch Dis Child. 1994;71:123–127. doi: 10.1136/adc.71.2.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zeevaert R, Foulquier F, Jaeken J, Matthijs G. Deficiencies in subunits of the conserved oligomeric Golgi complex define a novel group of Congenital Disorders of Glycosylation. Mol Genet Metab. 2008;93:15–21. doi: 10.1016/j.ymgme.2007.08.118. [DOI] [PubMed] [Google Scholar]
- 10.Kornak U, Reynders E, Dimopoulou A, et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet. 2008;40:32–34. doi: 10.1038/ng.2007.45. [DOI] [PubMed] [Google Scholar]
- 11.De Praeter CM, Gerwig GJ, Bause E, et al. A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. Am J Hum Genet. 2000;66:1744–1756. doi: 10.1086/302948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Jaeken J, Hennet T, Freeze H, Matthijs G. On the nomenclature of Congenital Disorders of Glycosylation (CDG) J Inherit Metab Dis. 2008;31:669–672. doi: 10.1007/s10545-008-0983-x. [DOI] [PubMed] [Google Scholar]