A Novel Type of Macrothrombocytopenia Associated with a Defect in α2,3-sialylation

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2011 Aug 26

PMID 21864493

Citations 18

Authors

Claire Jones

Jonas Denecke

Ronald Strater

Torsten Stolting

Yvonne Schunicht

Dagmar Zeuschner

Judith Klumperman

Dirk J Lefeber

Oliver Spelten

Alexander Zarbock

Sorge Kelm

Karen Strenge

Stuart M Haslam

Kerstin Luhn

Dorothea Stahl

Luca Gentile

Thomas Schreiter

Philip Hilgard

Annette G Beck-Sickinger

Thorsten Marquardt

Martin K Wild

Affiliations

Soon will be listed here.

Abstract

We describe a novel type of human thrombocytopenia characterized by the appearance of giant platelets and variable neutropenia. Searching for the molecular defect, we found that neutrophils had strongly reduced sialyl-Lewis X and increased Lewis X surface expression, pointing to a deficiency in sialylation. We show that the glycosylation defect is restricted to α2,3-sialylation and can be detected in platelets, neutrophils, and monocytes. Platelets exhibited a distorted structure of the open canalicular system, indicating defective platelet generation. Importantly, patient platelets, but not normal platelets, bound to the asialoglycoprotein receptor (ASGP-R), a liver cell-surface protein that removes desialylated thrombocytes from the circulation in mice. Taken together, this is the first type of human thrombocytopenia in which a specific defect of α2,3-sialylation and an induction of platelet binding to the liver ASGP-R could be detected.

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References

Sasaki K, Watanabe E, Kawashima K, Sekine S, Dohi T, Oshima M . Expression cloning of a novel Gal beta (1-3/1-4) GlcNAc alpha 2,3-sialyltransferase using lectin resistance selection. J Biol Chem. 1993; 268(30):22782-7. View

Kunishima S, Kamiya T, Saito H . Genetic abnormalities of Bernard-Soulier syndrome. Int J Hematol. 2002; 76(4):319-27. DOI: 10.1007/BF02982690. View

Greenberg J, Packham M, Cazenave J, Reimers H, Mustard J . Effects on platelet function of removal of platelet sialic acid by neuraminidase. Lab Invest. 1975; 32(4):476-84. View

Okajima T, Fukumoto S, Miyazaki H, Ishida H, Kiso M, Urano T . Molecular cloning of a novel alpha2,3-sialyltransferase (ST3Gal VI) that sialylates type II lactosamine structures on glycoproteins and glycolipids. J Biol Chem. 1999; 274(17):11479-86. DOI: 10.1074/jbc.274.17.11479. View

Kelm S, Pelz A, Schauer R, Filbin M, Tang S, de Bellard M . Sialoadhesin, myelin-associated glycoprotein and CD22 define a new family of sialic acid-dependent adhesion molecules of the immunoglobulin superfamily. Curr Biol. 1994; 4(11):965-72. DOI: 10.1016/s0960-9822(00)00220-7. View

Helmus Y, Denecke J, Yakubenia S, Robinson P, Luhn K, Watson D . Leukocyte adhesion deficiency II patients with a dual defect of the GDP-fucose transporter. Blood. 2006; 107(10):3959-66. DOI: 10.1182/blood-2005-08-3334. View

Etzioni A, Frydman M, Pollack S, Avidor I, Phillips M, Paulson J . Brief report: recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl J Med. 1992; 327(25):1789-92. DOI: 10.1056/NEJM199212173272505. View

Nurden A, Caen J . Specific roles for platelet surface glycoproteins in platelet function. Nature. 1975; 255(5511):720-2. DOI: 10.1038/255720a0. View

Pukel C, LLOYD K, Travassos L, Dippold W, Oettgen H, Old L . GD3, a prominent ganglioside of human melanoma. Detection and characterisation by mouse monoclonal antibody. J Exp Med. 1982; 155(4):1133-47. PMC: 2186649. DOI: 10.1084/jem.155.4.1133. View

10.

Kranz C, Jungeblut C, Denecke J, Erlekotte A, Sohlbach C, Debus V . A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy. Am J Hum Genet. 2007; 80(3):433-40. PMC: 1821118. DOI: 10.1086/512130. View

11.

Frommhold D, Ludwig A, Bixel M, Zarbock A, Babushkina I, Weissinger M . Sialyltransferase ST3Gal-IV controls CXCR2-mediated firm leukocyte arrest during inflammation. J Exp Med. 2008; 205(6):1435-46. PMC: 2413039. DOI: 10.1084/jem.20070846. View

12.

Niehues R, Hasilik M, Alton G, Korner C, Koch H, Zimmer K . Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest. 1998; 101(7):1414-20. PMC: 508719. DOI: 10.1172/JCI2350. View

13.

David R, Machova Z, Beck-Sickinger A . Semisynthesis and application of carboxyfluorescein-labelled biologically active human interleukin-8. Biol Chem. 2004; 384(12):1619-30. DOI: 10.1515/BC.2003.180. View

14.

Treichel U, Schreiter T, Meyer zum Buschenfelde K, Stockert R . High-yield purification and characterization of human asialoglycoprotein receptor. Protein Expr Purif. 1995; 6(3):251-5. DOI: 10.1006/prep.1995.1032. View

15.

Martinez-Duncker I, Dupre T, Piller V, Piller F, Candelier J, Trichet C . Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter. Blood. 2004; 105(7):2671-6. DOI: 10.1182/blood-2004-09-3509. View

16.

Sorensen A, Rumjantseva V, Nayeb-Hashemi S, Clausen H, Hartwig J, Wandall H . Role of sialic acid for platelet life span: exposure of beta-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor-expressing liver macrophages and hepatocytes. Blood. 2009; 114(8):1645-54. PMC: 2731641. DOI: 10.1182/blood-2009-01-199414. View

17.

Kuwano Y, Spelten O, Zhang H, Ley K, Zarbock A . Rolling on E- or P-selectin induces the extended but not high-affinity conformation of LFA-1 in neutrophils. Blood. 2010; 116(4):617-24. PMC: 3324292. DOI: 10.1182/blood-2010-01-266122. View

18.

Seri M, Cusano R, Gangarossa S, Caridi G, Bordo D, Lo Nigro C . Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium. Nat Genet. 2000; 26(1):103-5. DOI: 10.1038/79063. View

19.

Ellies L, Ditto D, Levy G, Wahrenbrock M, Ginsburg D, Varki A . Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands. Proc Natl Acad Sci U S A. 2002; 99(15):10042-7. PMC: 126621. DOI: 10.1073/pnas.142005099. View

20.

Jenkins C, Phillips D, Clemetson K, Meyer D, LARRIEU M, LUSCHER E . Platelet membrane glycoproteins implicated in ristocetin-induced aggregation. Studies of the proteins on platelets from patients with Bernard-Soulier syndrome and von Willebrand's disease. J Clin Invest. 1976; 57(1):112-24. PMC: 436631. DOI: 10.1172/JCI108251. View