title: Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme.
abstract: Heparin is a sulphated polysaccharide, synthesized exclusively by connective-tissue-type mast cells and stored in the secretory granules in complex with histamine and various mast-cell proteases. Although heparin has long been used as an antithrombotic drug, endogenous heparin is not present in the blood, so it cannot have a physiological role in regulating blood coagulation. The biosynthesis of heparin involves a series of enzymatic reactions, including sulphation at various positions. The initial modification step, catalysed by the enzyme glucosaminyl N-deacetylase/N-sulphotransferase-2, NDST-2, is essential for the subsequent reactions. Here we report that mice carrying a targeted disruption of the gene encoding NDST-2 are unable to synthesize sulphated heparin. These NDST-2-deficient mice are viable and fertile but have fewer connective-tissue-type mast cells; these cells have an altered morphology and contain severely reduced amounts of histamine and mast-cell proteases. Our results indicate that one site of physiological action for heparin could be inside connective-tissue-type mast cells, where its absence results in severe defects in the secretory granules.
authors.affiliation: Department of Cell and Molecular Biology, University of Uppsala, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Forsberg
authors.forename: G
authors.initials: G
authors.lastname: Pejler
authors.forename: M
authors.initials: M
authors.lastname: Ringvall
authors.forename: C
authors.initials: C
authors.lastname: Lunderius
authors.forename: B
authors.initials: B
authors.lastname: Tomasini-Johansson
authors.forename: M
authors.initials: M
authors.lastname: Kusche-Gullberg
authors.forename: I
authors.initials: I
authors.lastname: Eriksson
authors.forename: J
authors.initials: J
authors.lastname: Ledin
authors.forename: L
authors.initials: L
authors.lastname: Hellman
authors.forename: L
authors.initials: L
authors.lastname: Kjellén
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D053818:Chymases; D003433:Crosses, Genetic; D005260:Female; D018390:Gene Targeting; D005838:Genotype; D006493:Heparin / Q000096:biosynthesis* / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009504:Neutrophils / Q000276:immunology; D010537:Peritoneum / Q000473:pathology; D012697:Serine Endopeptidases / Q000378:metabolism; D013234:Stem Cells; D013431:Sulfates / Q000378:metabolism; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D013431:Sulfates; D007073:Immunoglobulin E; D006493:Heparin; C491855:Ndst2 protein, mouse; D015238:Sulfotransferases; D012697:Serine Endopeptidases; D053818:Chymases; D000581:Amidohydrolases