Summary
Congenital disorders of glycosylation (CDG) represent a group of inherited multiorgan diseases caused by defects in the biosynthesis of glycoproteins. We report on two dysmorphic siblings with severe liver disease who died at the age of a few weeks. Increased activities of lysosomal enzymes in plasma were found, though total sialic acid in plasma was strongly decreased. Isoelectric focusing of serum sialotransferrins showed a type 2-like CDG pattern. Some of the known CDG subtypes were excluded. O-Glycosylation was investigated by isoelectric focusing of apolipoprotein C-III, which showed increased fractions of hyposialylated isoforms. In a consecutive study a defect in the conserved oligomeric Golgi complex was established at the level of subunit COG-7, leading to disruption of multiple glycosylation functions of the Golgi. This report on patients with a new variant of CDG, due to a multiple Golgi defect, emphasizes in addition to sialotransferrins the importance of analysis of a serum O-linked glycoprotein, e.g. apolipoprotein C-III, in unclassified CDG-X cases.
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Barone R, Carchon H, Jansen E, et al (1998) Lysosomal enzyme activities in serum and leukocytes from patients with carbohydrate-deficient glycoprotein syndrome type IA (phosphomannomutase deficiency). J Inherit Metab Dis 21: 167–172.
Beltran-Valero de Bernabé D, Currier S, Steinbrecher A, et al (2002) Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker–Warburg syndrome. Am J Hum Genet 71: 1033–1043.
Cantor AB, Baranski TJ, Kornfeld S (1992) Lysosomal enzyme phosphorylation. II. Protein recognition determinants in either lobe of procathepsin D are sufficient for phosphorylation of both the amino and carboxyl lobe oligosaccharides. J Biol Chem 267: 23349–23356.
Chantret I, Dancourt J, Dupre T, et al (2003) A deficiency in dolichyl-P-glucose:Glc1 Man9GlcNAc2-PP-dolichyl alpha3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation. J Biol Chem 278: 9962–9971.
de Koning TJ, Borland L, van Diggelen OP, et al (1998) A novel disorder of N-glycosylation due to phosphomannose isomerase deficiency. Biochem Biophys Res Commun 245: 38–42.
De Praeter CM, Gerwig GJ, Bause E, et al (2000) A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. Am J Hum Genet 66: 1744–1756.
Frank CG, Grubenmann CE, Eyaid W, Berger EG, Aebi M, Hennet T (2004) Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL. Am J Hum Genet 75: 146–150.
Ghosh P, Griffith J, Geuze HJ, Kornfeld S (2003) Mammalian GGAs act together to sort mannose 6-phosphate receptors. J Cell Biol 163: 755–766.
Grubenmann CE, Frank CG, Hulsmeier AJ, et al (2004) Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik. Hum Mol Genet 13: 535–542.
Grunewald S, Imbach T, Huijben K, et al (2000) Clinical and biochemical characteristics of congenital disorder of glycosylation type Ic, the first recognized endoplasmic reticulum defect in N-glycan synthesis. Ann Neurol 47: 776–781.
Hanßke B, Thiel C, Lubke T, et al (2002) Deficiency of UDP-galactose:N-acetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId. J Clin Invest 109: 725–733.
Hayakawa K, De Felice C, Watanabe T (1993) Determination of free N-acetylneuraminic acid in human body fluids by high-performance liquid chromatography with fluorimetric detection. J Chromatogr 620: 25–31.
Imbach T, Schenk B, Schollen E, et al (2000) Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie. Clin Invest 105: 233–239.
Jaeken J (2003) Komrower Lecture. Congenital disorders of glycosylation (CDG): It’s all in it! J Inherit Metab Dis 26: 99–118.
Jaeken J, De Cock P, Stibler H, et al (1993) Carbohydrate-deficient glycoprotein syndrome type II. J Inherit Metab Dis 16: 1041.
Jaeken J, Kint J, Spaapen L (1992) Serum lysosomal enzyme abnormalities in galactosaemia. Lancet 340: 1472–1473.
Jaeken J, Schachter H, Carchon H, De Cock P, Coddeville B, Spik G (1994) Carbohydrate deficient glycoprotein syndrome type II: a deficiency in Golgi localised N-acetyl-glucosaminyltransferase II. Arch Dis Child 71: 123–127.
Korner C, Knauer R, Stephani U, Marquardt T, Lehle L, von Figura K (1999). Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase. EMBO J 18: 6816–6822.
Kranz C, Denecke J, Lehrman MA, et al (2001) A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If). J Clin Invest 108: 1613–1619.
Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K (1998) The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem 273: 26265–26268.
Lubke T, Marquardt T, Etzioni A, Hartmann E, von Figura K, Korner C (2001) Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency. Nature Genetics 28: 73–76.
Marquardt T, Denecke J (2003) Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 162: 359–379.
Quentin E, Gladen A, Roden L, Kresse H (1990) A genetic defect in the biosynthesis of dermatan sulfate proteoglycan: galactosyltransferase I deficiency in fibroblasts from a patient with a progeroid syndrome. Proc Natl Acad Sci USA 87: 1342–1346.
Thiel C, Schwarz M, Hasilik M, et al (2002) Deficiency of dolichyl-P-Man:Man7GlcNAc2-PP-dolichyl mannosyltransferase causes congenital disorder of glycosylation type Ig. Biochem J 367: 195–201.
Thiel C, Schwarz M, Peng J, et al (2003) A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. Biol Chem 278: 22498–22505.
Ungar D, Oka T, Brittle EE, et al (2002) Characterization of a mammalian Golgi-localized protein complex, COG, that is required for normal Golgi morphology and function. Cell Biol 157: 405–415.
Van Eijk HG, van Noort WL, Kroos MJ, van der Heul C (1982) The heterogeneity of human serum transferrin and human transferrin preparations on isoelectric focusing gels; no functional difference of the fractions in vitro. Clin Chim Acta 121: 209–216.
Van Schaftingen E, Jaeken J (1995) Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett 377: 318–320.
Wopereis S, Grunewald S, Morava E, et al (2003) Apolipoprotein C-III isofocusing in the diagnosis of genetic defects in O-glycan biosynthesis. Clin Chem 49: 1839–1845.
Wu X, Rush JS, Karaoglu D, et al (2003) Deficiency of UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1 phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation type Ij. Hum Mutat 22: 144–150.
Wu X, Steet RA, Bohorov O, et al (2004) Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nature Medicine 10: 518–523.
Yoshida A, Kobayashi K, Manya H, et al (2001) Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 1: 717–724.
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Spaapen, L.J.M., Bakker, J.A., van der Meer, S.B. et al. Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder. J Inherit Metab Dis 28, 707–714 (2005). https://doi.org/10.1007/s10545-005-0015-z
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DOI: https://doi.org/10.1007/s10545-005-0015-z