A Missense Mutation (Tyr88 to Cys) in the Platelet Membrane Glycoprotein Ibβ Gene Affects GPIb/IX Complex Expression

Yumi Kurokawa; Fumihiro Ishida; Takehiko Kamijo; Shinji Kunishima; Dermot Kenny; Kiyoshi Kitano; Kenichi Koike

doi:10.1055/s-0037-1616058

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 86(05): 1249-1256
DOI: 10.1055/s-0037-1616058

Review Article

Schattauer GmbH

A Missense Mutation (Tyr88 to Cys) in the Platelet Membrane Glycoprotein Ibβ Gene Affects GPIb/IX Complex Expression

Bernard-Soulier Syndrome in the Homozygous Form and Giant Platelets in the Heterozygous Form

Yumi Kurokawa

¹Department of Pediatrics, Matsumoto, Japan

,

Fumihiro Ishida

²Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan

,

Takehiko Kamijo

¹Department of Pediatrics, Matsumoto, Japan

,

Shinji Kunishima

³Japanese Red Cross Aichi Blood Center, Seto, Japan

,

Dermot Kenny

⁴Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland

,

Kiyoshi Kitano

²Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan

,

Kenichi Koike

¹Department of Pediatrics, Matsumoto, Japan

› Author Affiliations

Abstract

Summary

This study examined the molecular basis of a missense mutation of the platelet glycoprotein (GP) Ibβ gene in two families. In the propositus with a novel form of Bernard-Soulier syndrome (BSS) from Family I, only GPIbα was detectable in reduced amounts on platelet surfaces by flow cytometry. There were no GPIX or GPIbβ found by immunoblotting. DNA sequencing analysis showed a homozygous mutation in the GPIbβ gene which changed Tyr (TAC) to Cys (TGC) at residue 88. Her parents were heterozygous for Tyr88Cys in the GPIbβ gene. In transient transfection studies on 293T cells, both Tyr88Cys and Tyr88Ala mutations suppressed the expression of GPIb/IX complexes. In addition, Tyr88Cys GPIbβ mutation was found to exert a dominant negative effect on the GPIb expression.

Five individuals from Family II, four of whom reported elsewhere as having giant platelet disorders with normal aggregation (BLOOD, 1997; 89: 2404) and one newly analyzed in this study, were heterozygous for Tyr88Cys in the GPIb gene. Microsatellite analysis of chromosome 22 showed a common haplotype in 8 of the individuals with Tyr88Cys mutations in Families I and II. Tyr88 in the GPIbβ gene plays a significant role in the GPIb/IX expression; the defect causes BSS in a homozygous form and possibly giant platelets in a heterozygous form.

Keywords

Bernard-Soulier syndrome - platelet glycoprotein - Ibbeta - missense mutation - dominant negative

Full Text

References

References
1 Nurden AT, Caen JP. Specific roles for platelet surface glycoproteins in platelet function. Nature 1975; 255: 720-22.
2 Clementson KJ, Mcgregor JL, James E, Dechavanne M, Luscher EF. Characterization of the platelet membrane glycoprotein abnormalities in Bernard-Soulier syndrome and comparison with normal by surface-labeling techniques and high-resolution two-dimensional gel electrophoresis. J Clin Invest 1982; 70: 304-11.
3 Berndt MC, Gregory C, Chong BH, Zola H, Castaldi PA. Additional glycoprotein defects in Bernard-Soulier’s syndrome. Confirmation of genetic basis by parental analysis. Blood 1983; 62: 800-7.
4 Berndt MC, Fournier DJ, Castaldi PA. Bernard-Soulier syndrome. Baillieres Clin Haematol 1989; 2: 585-607.
5 Rome GM, Dong JF, Lopez JA. The Glycoprotein Ib/IX complex is a platelet counter receptor for P-selectin. J Exp Med 1999; 190: 803-13.
6 Simon DI, Chen Z, Li CQ, Dong JF, Mclntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC, Lopez JA. Platelet glycoprotein Ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192: 193-204.
7 Caen JP, Levy-Toledano S. Interaction between platelets and von Wille-brand factor provides a new scheme for primary haemostasis. Nat New Biol 1973; 244: 159-60.
8 Wu G, Meloni FJ, Shapiro SS. Platelet glycoprotein(GP) IX associates with GPIbα in the platelet membrane GPIb complex. Blood 1996; 87: 2782-87.
9 Lopez JA, Weisman S, Sanan DA, Sih T, Chambers M, Li CQ. Glycoprotein(GP) Ibβ is the critical subunit linking GPIb and GPIX in the GPIb-complex. J Biol Chem 1994; 269: 23716-21.
10 Modderman PW, Admiraal LG, Sonnenberg A, von dem Borne AE. Glycoproteins V and Ib-IX form a noncovalent complex in the platelet membrane. J Biol Chem 1992; 267: 364-69.
11 Kobe B, Deisenhofer J. The leucine-rich repeat: A versatile binding motif. Trends Biochem Sci 1994; 19: 415-21.
12 Lopez JA. The platelet glycoprotein Ib-IX complex. Blood Coagul Fibrinolysis 1994; 5: 97-119.
13 Kunishima S, Lopez JA, Kobayashi S, Imai N, Kamiya T, Saito H, Naoe T. Missense mutations of the glycoprotein(GP) Ib gene impairing the GPIb α/β disulfide linkage in a family with giant platelet disorder. Blood 1997; 89: 2404-12.
14 Kenny D, Morateck PA, Gill JC, Montgomery RR. The interaction of Glycoprotein(GP) Ibβ with GPIX- A genetic Cause of Bernard-Soulier Syndrome. Blood 1999; 93: 2968-75.
15 Bernard J, Soulier JP. Sur une nouvelle variete de dystrophie thrombocytaire thrombocytaire hemorragipare congenitale. Semaine des Hopitaux de Paris 1948; 24: 3217.
16 Roth GJ. Developing relationships. Arterial platelet adhesion, glycoprotein Ib, and leucine-rich glycoproteins. Blood 1991; 77: 5-19.
17 Ruggeri ZM, Marco LD, Gatti L, Bader R, Montgomery RR. Platelets have more than one binding site for von Willebrand factor. J Clin Invest 1983; 72: 1-12.
18 Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier Syndrome. Blood 1998; 91: 4397-418.
19 Ludlow LB, Schick BP, Konkle BA. Identification of a mutation in a GATA binding site of the platelet glycoprotein Ib promoter resulting in the Bernard-Soulier syndrome. J Biol Chem 1996; 271: 22076-80.
20 Moran N, Morateck PA, Kenny D. Surface expression of glycoprotein Ib is dependent on glycoprotein Ib : evidence from a novel mutation causing Bernard-Soulier syndrome. Blood 2000; 96: 532-9.
21 Kunishima S, Tomiyama Y, Saito H. Homozygous Pro74→Arg mutation in the platelet glycoprotein Ib gene associated with Bernard-Soulier syndrome. Thromb Haemost 2000; 84: 112-7.
22 Ishida F, Saji H, Maruya E, Furihata K. Human platelet-specific antigen, Sib^a, is associated with the molecular weight polymorphism of glycoprotein Ib alpha. Blood 1991; 78: 1722-9.
23 Ishida F, Furihata K, Ishida K, Yan J, Kitano K, Kiyosawa K, Furuta S. The largest variant of platelet glycoprotein Ib has four tandem repeats of 13 amino acids in the macroglycopeptide region and a genetic linkage with methionine¹⁴⁵ . Blood 1995; 86: 1357-60.
24 Li C, Martin SE, Roth GJ. The genetic defect in two well studied cases of Bernard-Soulier syndrome: a point mutation in the fifth leucine-rich repeat of platelet glycoprotein Ib. Blood 1995; 86: 3805-14.
25 Wright SD, Michaelides K, Johonson DJ, West NC, Tuddenham EG. Double heterozygosity for mutations in the platelet glycoprotein IX gene in three siblings with Bernard-Soulier syndrome. Blood 1993; 81: 2339-47.
26 Budarf ML, Konkle BA, Ludlow LB, Michaud D, Li M, Yamashiro DJ, McDonald-McGinn D, Zackai EH, Driscoll DA. Identification of a patient with Bernard-Soulier syndrome and a deletion in the DiGeorge/Velo-cardio-facial chromosomal region in 22q11.2. Hum Mol Genet 1995; 4: 763-6.
27 Crifasi PA, Micheles VV, Driscoll DJ, Jalal SM, Dewald GW. DNA fluorescent probes for diagnosis of velocardiofacial and related syndromes. Mayo Clin Proc 1995; 70: 1148-53.
28 Mlder MP, Wilke M, Langeveld A. Positional mapping of loci in the DiGeorge critical region at chromosome 22q11 using a new marker (D22S183). Hum Genet 1995; 96: 133-41.
29 Pear WS, Nolan GP, Scott ML, Baltimore D. Production of high-titer helper-free retroviruses by transient transfection. Proc Natl Acad Sci USA 1993; 90: 8392-96.
30 Chen C, Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol 1987; 7: 2745-52.
31 Wenger RH, Kieffer N, Wicki AN, Clemetson KJ. Structure of the human blood platelet membrane glycoprotein Ib gene. Biochem Biophys Res Commun 1998; 156: 389-95.
32 Hickey MJ, Roth GJ. Characterization of the gene encoding human blood platelet glycoprotein IX. J Biol Chem 1993; 268: 3438-43.
33 Yagi M, Edelhoff S, Disteche CM, Roth GJ. Structural characterization and chromosomal location of the gene encoding human platelet glycoprotein Ib beta. J Biol Chem 1994; 269: 17424-7.
34 Dong JF, Gao S, Lopez JA. Synthesis, assembly, and intracellular transport of the platelet glycoprotein Ib-IX-V complex. J Biol Chem 1998; 273: 31449-54.
35 Lopez JA, Chung DW, Fujikawa K, Hangen FS, Davie EW, Roth GJ. The alpha and beta chains of human platelet glycoprotein Ib are both transmembrane proteins containing a leucine-rich amino acid sequence. Proc Natl Acad Sci USA 1988; 85: 2135-39.
36 Kalomiris EL, Coller BS. Thiol-specific probes indicate the a the β-chain of platelet glycoprotein Ib is a transmembrane protein with a reactive endo-facial sulfhydryl group. Biochemistry 1985; 24: 5430-36.
37 Savoia A, Balduini CB, Savino M, Noris P, Vecchio MD, Perrotta S, Belletti S, Poggi V, Iolascon A. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome. Blood 2001; 97: 1330-35.