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Title: Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development

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{r_arrow}Phe and the other having His{r_arrow}Arg) in the catalytic domain of the gene MGAT2, encoding UDP-GlcNAc:{alpha}-6-D-mannoside {Beta}-1,2-N-ace-tylglucosaminyltransferase 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. 38 refs., 4 figs., 1 tab.

Authors:
; ;  [1]
  1. Univ. of Toronto (Canada) [and others
Publication Date:
OSTI Identifier:
476750
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Journal of Human Genetics; Journal Volume: 59; Journal Issue: 4; Other Information: PBD: Oct 1996
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; GENES; GENE MUTATIONS; GENE REGULATION; GENETIC MAPPING; BRAIN; ONTOGENESIS; ENZYMES; ENZYME ACTIVITY; PATIENTS; HEREDITARY DISEASES; METABOLIC DISEASES; CONGENITAL DISEASES; HUMAN CHROMOSOME 14; GLYCOPROTEINS; CARBOHYDRATES; RECESSIVE MUTATIONS; AMINO ACIDS; BIOSYNTHESIS; OLIGONUCLEOTIDES; POLYMERASE CHAIN REACTION

Citation Formats

Tan, J., Schachter, H., and Dunn, J.. Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development. United States: N. p., 1996. Web.
Tan, J., Schachter, H., & Dunn, J.. Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development. United States.
Tan, J., Schachter, H., and Dunn, J.. 1996. "Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development". United States. doi:.
@article{osti_476750,
title = {Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development},
author = {Tan, J. and Schachter, H. and Dunn, J.},
abstractNote = {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{r_arrow}Phe and the other having His{r_arrow}Arg) in the catalytic domain of the gene MGAT2, encoding UDP-GlcNAc:{alpha}-6-D-mannoside {Beta}-1,2-N-ace-tylglucosaminyltransferase 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. 38 refs., 4 figs., 1 tab.},
doi = {},
journal = {American Journal of Human Genetics},
number = 4,
volume = 59,
place = {United States},
year = 1996,
month =
}
  • Carbohydrate-deficient glycoprotein syndrome type I (CDG I) is characterized clinically by severe nervous system involvement and biochemically by defects in the carbohydrate residues in a number of serum glycoproteins. The CDG1 gene was recently localized by us to a 13-cM interval in chromosome region 16p13. In this study 44 CDG I families from nine countries were analyzed with available markers in a region ranging from marker D16S495 to D16S497, and haplotype and linkage disequilibrium analyses were performed. One specific haplotype was found to be markedly overrepresented in CDG I patients from a geographically distinct region in Scandinavia, strongly indicating thatmore » CDG I families in this region share the same ancestral CDG1 mutation. Furthermore, analysis of the extent of the common haplotype in these families indicates that the CDG1 gene is located in the region defined by markers D16S513-AFMa284wd5-Dl6S768-Dl6S406-D16S502. The critical CDG1 region, in strong linkage disequilibrium with markers AFMa284wd5, D16S768, and D16S406, thus constitutes less than 1 Mb of DNA and less than 1 cM in the very distal part of the CDG1 region defined by us previously. 14 refs., 3 figs., 2 tabs.« less
  • No abstract prepared.
  • Carbohydrate-deficient glycoprotein syndrome type I is a multisystem disease with early severe nervous system involvement. The disease, which is inherited as a recessive autosomal trait, is biochemically characterized by complex defects in the terminal carbohydrate residues of a number of serum glycoproteins. This can be most readily detected in transferrin. A whole genome scan was initiated in order to try localizing the gene (CDG1) with linkage technique. We therefore analyzed 25 CDG1-pedigrees with several highly polymorphic microsatellite markers and after exclusion of about 30% of the genome, linkage was detected with markers located in chromosome region 16p. The lod scoremore » (Zmax) was above 8 (theta=0.00) for several markers in the region. In order to further sublocalize the CDG1 gene, recombination and linkage disequilibrium analyses were performed. Recombination events in some pedigrees indicated that the CDG1 gene is located in a 13 cM interval between microsatellite markers D16S406 and D16S500. Furthermore, allelic association was shown for marker D16S406, indicating that the CDG1 gene is located close to this. No heterogeneity could be detected in the European family material tested by us.« less
  • We have analyzed a series of polymorphic markers on chromosome 16p13 in 17 families with carbohydrate-deficient glycoprotein syndrome type I (CDG1). First, linkage to the region between D15S406 and D16S500 is confirmed. The telomeric border of the candidate region is now definitively placed proximal to D16S406 by crossovers observed in 2 families. Second, in 1 family with affected siblings, the disease is not linked to chromosome 16p. Genetic heterogeneity has not been previously reported for CDG1, and this observation has implications for prenatal diagnosis. Third, allelic associations suggest that the disease locus is localized close to D16S414/D16S497. This places themore » region of interest centromeric of its published localization. 11 refs., 1 fig., 2 tabs.« less
  • Waardenburg syndrome type I (WS-I) is an autosomal dominant disorder characterized by sensorineural hearing loss, dystopia canthorum, pigmentary disturbances, and other developmental defects. Klein-Waardenburg syndrome (WS-III) is a disorder with many of the same characteristics as WS-I and includes musculoskeletal abnormalities. The authors have recently reported the identification and characterization of one of the first gene defects, in the human PAX3 gene, which causes WS-I. PAX3 is a DNA-binding protein that contains a structural motif known as the paired domain and is believed to regulate the expression of other genes. In this report they describe two new mutations, in themore » human PAX3 gene, that are associated with WS. One mutation was found in a family with WS-I, while the other mutation was found in a family with WS-III. Both mutations were in the highly conserved paired domain of the human PAX3 gene and are similar to other mutations that cause WS. The results indicate that mutations in the PAX3 gene can cause both WS-I and WS-III. 36 refs., 4 figs.« less