Journal Article

Incomplete Synthesis of N-Glycans in Congenital Dyserythropoietic Anemia Type II Caused by a Defect in the Gene Encoding α-Mannosidase II

Dell, Anne, Moremen, Kelley W., Fukuda, Michiko N., Luzzatto, Lucio, Masri, Khaled A.

1990

Overview

Congenital dyserythropoietic anemia type II, or hereditary erythroblastic multinuclearity with a positive acidified-serum-lysis test (HEMPAS), is a genetic anemia in humans inherited by an autosomally recessive mode. The enzyme defect in most HEMPAS patients has previously been proposed as a lowered activity of N-acetylglucosaminyltransferase II, resulting in a lack of polylactosamine on proteins and leading to the accumulation of polylactosaminyl lipids. A recent HEMPAS case, G.C., has now been analyzed by cell-surface labeling, fast-atom-bombardment mass spectrometry of glycopeptides, and activity assay of glycosylation enzymes. Significantly decreased glycosylation of polylactosaminoglycan proteins and incompletely processed asparagine-linked oligosaccharides were detected in the erythrocyte membranes of G.C. In contrast to the earlier studied HEMPAS cases, G.C. cells are normal in N-acetylglucosaminyltransferase II activity but are low in α-mannosidase II (α-ManII) activity. Northern (RNA) analysis of poly(A)+mRNA from normal, G.C., and other unrelated HEMPAS cells all showed double bands at the 7.6-kilobase position, detected by an α-ManII cDNA probe, but expression of these bands in G.C. cells was substantially reduced (<10% of normal). In Southern analysis of G.C. and normal genomic DNA, the restriction fragment patterns detected by the α-ManII cDNA probe were indistinguishable. These results suggest that G.C. cells contain a mutation in α-ManII-encoding gene that results in inefficient expression of α-ManII mRNA, either through reduced transcription or message instability. This report demonstrates that HEMPAS is caused by a defective gene encoding an enzyme necessary for the synthesis of asparagine-linked oligosaccharides.

• Publisher: National Academy of Sciences of the United States of America,National Acad Sciences
• Subject: 550201 - Biochemistry- Tracer Techniques / Anemia / Anemia, Dyserythropoietic, Congenital - blood / Anemia, Dyserythropoietic, Congenital - enzymology / Anemia, Dyserythropoietic, Congenital - genetics / ANEMIAS / Anemias. Hemoglobinopathies / BASIC BIOLOGICAL SCIENCES / Biological and medical sciences / BIOSYNTHESIS / Carbohydrate Conformation / Carbohydrate Sequence / CARBOHYDRATES / Cell Membrane - enzymology / Complementary DNA / CONGENITAL DISEASES / DISEASES / Diseases of red blood cells / DNA / DNA Probes / ENZYMES / Erythrocyte membrane / Erythrocytes / GENE MUTATIONS / Genes / Genomics / GLYCOLIPIDS / Glycopeptides - isolation & purification / GLYCOPROTEINS / GLYCOSYL TRANSFERASES / Hematologic and hematopoietic diseases / HEMIC DISEASES / HEREDITARY DISEASES / Humans / Kinetics / LIPIDS / Lymphocytes - enzymology / Mannosidases - blood / Mannosidases - deficiency / Mannosidases - genetics / MASS SPECTRA / Medical sciences / Messenger RNA / METABOLIC DISEASES / Molecular Sequence Data / Mutation / MUTATIONS / NUCLEIC ACIDS / OLIGOSACCHARIDES / Oligosaccharides - chemical synthesis / ORGANIC COMPOUNDS / PATIENTS / Polysaccharides - biosynthesis / PROTEINS / RECESSIVE MUTATIONS / RECOMBINANT DNA / RNA / SACCHARIDES / SPECTRA / Spectrometry, Mass, Fast Atom Bombardment / SYMPTOMS / SYNTHESIS / TRANSFERASES