Abstract
Carbohydrate-deficient glycoprotein syndrome (CDGS) type II is a multisystemic congenital disease with severe involvement of the nervous system. Two unrelated CDGS type II patients are shown to have point mutations (one patient having Ser-->Phe and the other having His-->Arg) in the catalytic domain of the gene MGAT2, encoding UDP-GlcNAc:alpha-6-D-mannoside beta-1,2-N- acetylglucosaminyltransferase II (GnT II), an enzyme essential for biosynthesis of complex Asn-linked glycans. Both mutations caused both decreased expression of enzyme protein in a baculovirus/insect cell system and inactivation of enzyme activity. Restriction-endonuclease analysis of DNA from 23 blood relatives of one of these patients showed that 13 donors were heterozygotes; the other relatives and 21 unrelated donors were normal homozygotes. All heterozygotes showed a significant reduction (33%-68%) in mononuclear-cell GnT II activity. The data indicate that CDGS type II is an autosomal recessive disease and that complex Asn-linked glycans are essential for normal neurological development.
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Selected References
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- Charuk J. H., Tan J., Bernardini M., Haddad S., Reithmeier R. A., Jaeken J., Schachter H. Carbohydrate-deficient glycoprotein syndrome type II. An autosomal recessive N-acetylglucosaminyltransferase II deficiency different from typical hereditary erythroblastic multinuclearity, with a positive acidified-serum lysis test (HEMPAS). Eur J Biochem. 1995 Jun 1;230(2):797–805. doi: 10.1111/j.1432-1033.1995.0797h.x. [DOI] [PubMed] [Google Scholar]
- Eggens I., Fenderson B., Toyokuni T., Dean B., Stroud M., Hakomori S. Specific interaction between Lex and Lex determinants. A possible basis for cell recognition in preimplantation embryos and in embryonal carcinoma cells. J Biol Chem. 1989 Jun 5;264(16):9476–9484. [PubMed] [Google Scholar]
- Fenderson B. A., Eddy E. M., Hakomori S. Glycoconjugate expression during embryogenesis and its biological significance. Bioessays. 1990 Apr;12(4):173–179. doi: 10.1002/bies.950120406. [DOI] [PubMed] [Google Scholar]
- Fenderson B. A., Zehavi U., Hakomori S. A multivalent lacto-N-fucopentaose III-lysyllysine conjugate decompacts preimplantation mouse embryos, while the free oligosaccharide is ineffective. J Exp Med. 1984 Nov 1;160(5):1591–1596. doi: 10.1084/jem.160.5.1591. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hagberg B. A., Blennow G., Kristiansson B., Stibler H. Carbohydrate-deficient glycoprotein syndromes: peculiar group of new disorders. Pediatr Neurol. 1993 Jul-Aug;9(4):255–262. doi: 10.1016/0887-8994(93)90060-p. [DOI] [PubMed] [Google Scholar]
- Hammond C., Helenius A. Quality control in the secretory pathway. Curr Opin Cell Biol. 1995 Aug;7(4):523–529. doi: 10.1016/0955-0674(95)80009-3. [DOI] [PubMed] [Google Scholar]
- Ioffe E., Stanley P. Mice lacking N-acetylglucosaminyltransferase I activity die at mid-gestation, revealing an essential role for complex or hybrid N-linked carbohydrates. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):728–732. doi: 10.1073/pnas.91.2.728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jaeken J., Carchon H., Stibler H. The carbohydrate-deficient glycoprotein syndromes: pre-Golgi and Golgi disorders? Glycobiology. 1993 Oct;3(5):423–428. doi: 10.1093/glycob/3.5.423. [DOI] [PubMed] [Google Scholar]
- Jaeken J., Carchon H. The carbohydrate-deficient glycoprotein syndromes: an overview. J Inherit Metab Dis. 1993;16(5):813–820. doi: 10.1007/BF00714272. [DOI] [PubMed] [Google Scholar]
- Jaeken J., De Cock P., Stibler H., Van Geet C., Kint J., Ramaekers V., Carchon H. Carbohydrate-deficient glycoprotein syndrome type II. J Inherit Metab Dis. 1993;16(6):1041–1041. doi: 10.1007/BF00711522. [DOI] [PubMed] [Google Scholar]
- Jaeken J., Schachter H., Carchon H., De Cock P., Coddeville B., Spik G. Carbohydrate deficient glycoprotein syndrome type II: a deficiency in Golgi localised N-acetyl-glucosaminyltransferase II. Arch Dis Child. 1994 Aug;71(2):123–127. doi: 10.1136/adc.71.2.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Knauer R., Lehle L., Hanefeld F., von Figura K. Normal N-oligosaccharyltransferase activity in fibroblasts from patients with carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis. 1994;17(5):541–544. doi: 10.1007/BF00711588. [DOI] [PubMed] [Google Scholar]
- Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
- Metzler M., Gertz A., Sarkar M., Schachter H., Schrader J. W., Marth J. D. Complex asparagine-linked oligosaccharides are required for morphogenic events during post-implantation development. EMBO J. 1994 May 1;13(9):2056–2065. doi: 10.1002/j.1460-2075.1994.tb06480.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Panneerselvam K., Freeze H. H. Enzymes involved in the synthesis of mannose-6-phosphate from glucose are normal in carbohydrate deficient glycoprotein syndrome fibroblasts. Biochem Biophys Res Commun. 1995 Mar 17;208(2):517–522. doi: 10.1006/bbrc.1995.1369. [DOI] [PubMed] [Google Scholar]
- Paulson J. C., Colley K. J. Glycosyltransferases. Structure, localization, and control of cell type-specific glycosylation. J Biol Chem. 1989 Oct 25;264(30):17615–17618. [PubMed] [Google Scholar]
- Powell L. D., Paneerselvam K., Vij R., Diaz S., Manzi A., Buist N., Freeze H., Varki A. Carbohydrate-deficient glycoprotein syndrome: not an N-linked oligosaccharide processing defect, but an abnormality in lipid-linked oligosaccharide biosynthesis? J Clin Invest. 1994 Nov;94(5):1901–1909. doi: 10.1172/JCI117540. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ramaekers V. T., Stibler H., Kint J., Jaeken J. A new variant of the carbohydrate deficient glycoproteins syndrome. J Inherit Metab Dis. 1991;14(3):385–388. doi: 10.1007/BF01811710. [DOI] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schachter H. Biosynthetic controls that determine the branching and microheterogeneity of protein-bound oligosaccharides. Biochem Cell Biol. 1986 Mar;64(3):163–181. doi: 10.1139/o86-026. [DOI] [PubMed] [Google Scholar]
- Stibler H., Stephani U., Kutsch U. Carbohydrate-deficient glycoprotein syndrome--a fourth subtype. Neuropediatrics. 1995 Oct;26(5):235–237. doi: 10.1055/s-2007-979762. [DOI] [PubMed] [Google Scholar]
- Stibler H., Westerberg B., Hanefeld F., Hagberg B. Carbohydrate-deficient glycoprotein (CDG) syndrome--a new variant, type III. Neuropediatrics. 1993 Feb;24(1):51–52. doi: 10.1055/s-2008-1071513. [DOI] [PubMed] [Google Scholar]
- Tan J., D'Agostaro A. F., Bendiak B., Reck F., Sarkar M., Squire J. A., Leong P., Schachter H. The human UDP-N-acetylglucosamine: alpha-6-D-mannoside-beta-1,2- N-acetylglucosaminyltransferase II gene (MGAT2). Cloning of genomic DNA, localization to chromosome 14q21, expression in insect cells and purification of the recombinant protein. Eur J Biochem. 1995 Jul 15;231(2):317–328. doi: 10.1111/j.1432-1033.1995.tb20703.x. [DOI] [PubMed] [Google Scholar]
- Van Schaftingen E., Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett. 1995 Dec 27;377(3):318–320. doi: 10.1016/0014-5793(95)01357-1. [DOI] [PubMed] [Google Scholar]
- Wada Y., Nishikawa A., Okamoto N., Inui K., Tsukamoto H., Okada S., Taniguchi N. Structure of serum transferrin in carbohydrate-deficient glycoprotein syndrome. Biochem Biophys Res Commun. 1992 Dec 15;189(2):832–836. doi: 10.1016/0006-291x(92)92278-6. [DOI] [PubMed] [Google Scholar]
- Yamashita K., Ideo H., Ohkura T., Fukushima K., Yuasa I., Ohno K., Takeshita K. Sugar chains of serum transferrin from patients with carbohydrate deficient glycoprotein syndrome. Evidence of asparagine-N-linked oligosaccharide transfer deficiency. J Biol Chem. 1993 Mar 15;268(8):5783–5789. [PubMed] [Google Scholar]
- Yamashita K., Ohkura T., Ideo H., Ohno K., Kanai M. Electrospray ionization-mass spectrometric analysis of serum transferrin isoforms in patients with carbohydrate-deficient glycoprotein syndrome. J Biochem. 1993 Dec;114(6):766–769. doi: 10.1093/oxfordjournals.jbchem.a124253. [DOI] [PubMed] [Google Scholar]
- Yasugi E., Nakasuji M., Dohi T., Oshima M. Major defect of carbohydrate-deficient-glycoprotein syndrome is not found in the synthesis of dolichyl phosphate or N-acetylglucosaminyl-pyrophosphoryl-dolichol. Biochem Biophys Res Commun. 1994 Apr 29;200(2):816–820. doi: 10.1006/bbrc.1994.1524. [DOI] [PubMed] [Google Scholar]