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.
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.
Tan
J
J
Department of Biochemistry Research, The Hospital for Sick Children, Toronto, Ontario, Canada.
Dunn
J
J
Jaeken
J
J
Schachter
H
H
D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000254:growth & development* / Q000503:physiopathology; D002648:Child; D018981:Congenital Disorders of Glycosylation / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008297:Male; D009000:Monocytes; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011134:Polysaccharides / Q000096:biosynthesis*; D015183:Restriction Mapping
D017931:DNA Primers; D011134:Polysaccharides; D017351:N-Acetylglucosaminyltransferases; C063313:alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase