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DOI: 10.1055/s-0038-1650640
Bernard-Soulier Syndrome with Severe Bleeding: Absent Platelet Glycoprotein lb alpha Due to a Homozygous One-base Deletion
Publication History
Received 02 October 1995
Accepted after revision 25 July 1996
Publication Date:
11 July 2018 (online)
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Summary
Bernard-Soulier syndrome is a rare congenital platelet disorder that affects a surface membrane adhesion receptor, glycoprotein (GP) Ib-V-IX. Both the genetic defects and the bleeding diatheses associated with the syndrome are heterogeneous due, in part, to the complexity of the involved receptor which consists of four different members, GPs: Ibα-Mr 143 K (contains the von Willebrand factor-binding site), Ibβ-Mr 22 K, V-Mr 83 K and IX-Mr 20 K. We studied a kindred that includes a 40 year-old man with severe Bernard-Soulier syndrome: life-threatening gastrointestinal bleeding, thrombocytopenia, giant platelets and absent ristocetin-dependent platelet aggregation. By Southern blotting, PCR amplification/sequencing, hetero-duplex analysis, and allele-specific oligonucleotide hybridization, the Ib-V-IX genes were analyzed, and the molecular genetic defect was defined as a one-base deletion in the GPIbα gene, involving an adenine of codon 19. The mutation, K19R, homozygous in the propositus and heterozygous in the available unaffected relatives, leads to a frame shift in codons 19-21 and a premature stop codon after codon 21. No functional GPIbα can be produced from the mutant allele, implying that the platelets of the affected patient lack all GPIbα. Within the spectrum of Bernard-Soulier syndrome, this patient’s disorder exemplifies a severe or “classic” extreme; an “experiment of Nature” that illustrates the effect of a complete deficiency of the ligand-binding chain (GPIbα) of the GPIb-V-IX receptor.
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References
- 1 Bernard J, Soulier JP. Sur une nouvelle variété de dystrophie thrombocytaire hemor-rhagipare congenitale. Sem Hop Paris 1948; 24: 3217-3223
- 2 Nurden AT, Caen JP. Specific roles for platelet surface glycoproteins in platelet function. Nature 1975; 255: 720-722
- 3 George JN, Nurden AT. Inherited disorders of the platelet membrane: Glanzmann’s thrombasthenia and Bernard-Soulier syndrome. In: Hemostasis and Thrombosis. Basic Principles and Clinical Practice Colman RW, Hirsh J, Marder VJ, Salzman EW. eds J.B.Lippincott Company; Philadelphia, PA: 1987: 726-754
- 4 Howard MA, Sawers RJ, Firkin BG. Ristocetin: A means of differentiating von Willebrand’s disease into two groups. Blood 1973; 41: 687-694
- 5 Weiss HJ, Tschopp TB, Baumgartner HR, Sussman II, Johnson MM, Egan JJ. Decreased adhesion of giant (Bernard-Soulier) platelets to sub-endothelium. Amer J Med 1974; 57: 920-925
- 6 Roth GJ. Developing relationships: Arterial platelet adhesion, glycoprotein lb, and leucine-rich glycoproteins. Blood 1991; 77: 5-19
- 7 Lopez JA, Chung DW, Fujikawa K, Hagen FS, Papayannopoulou T, Roth GJ. Cloning of the a chain of human platelet glycoprotein lb: A transmembrane protein with homology to leucine-rich α-2 -glycoprotein. Proc Natl Acad Sci USA 1987; 84: 5615-5619
- 8 Vicente V, Houghton RA, Ruggeri ZM. Identification of a site in the alpha chain of platelet glycoprotein lb that participates in von Willebrand factor binding. J Biol Chem 1991; 265: 274-280
- 9 Lopez JA, Chung DW, Fujikawa K, Hagen FS, Davie EW, Roth GJ. The α and β chains of human platelet glycoprotein lb are both trans-membrane proteins containing a leucine-rich amino acid sequence. Proc Natl Acad Sci USA 1988; 85: 2135-2139
- 10 Hickey MJ, Hagen FS, Yagi M, Roth GJ. Human platelet glycoprotein V: Characterization of the polypeptide and the related Ib-V-IX receptor sys-tem of adhesive, leucine-rich glycoproteins. Proc Natl Acad Sci USA 1993; 90: 8327-8331
- 11 Hickey MJ, Williams SA, Roth GJ. Human platelet glycoprotein IX: An adhesive prototype of leucine-rich glycoproteins with flank-center-flank structures. Proc Natl Acad Sci USA 1989; 86: 6773-6777
- 12 Takehashi N, Takehashi Y, Putnam FW. Periodicity of leucine and tandem repetition of a 24-amino acid segment in the primary structure of leucine-rich alpha 2-glycoprotein of human serum. Proc Natl Acad Sci USA 1985; 82: 1906-1910
- 13 Clemetson KJ, McGregor JL, Dechavanne M, Luscher EF. Characterization of the platelet membrane glycoprotein abnormalities in Bernard-Soulier syndrome and comparison with normal by surface-labelling techniques and high resolution twodimensional electrophoresis. J Clin Invest 1982; 70: 304-311
- 14 Wenger RH, Wicki AN, Kieffer N, Adolph S, Hameister H, Clemetson KJ. The 5’ flanking region and chromosomal localization of the gene encoding human platelet membrane glycoprotein Iba. Gene 1989; 85: 517-527
- 15 Hashimoto Y, Ware J. Identification of essential GATA and Ets binding motifs within the promoter of the platelet glycoprotein Iba gene. J Biol Chem 1995; 270: 24532-24539
- 16 Hickey MJ, Roth GJ. Characterization of the gene encoding human platelet glycoprotein IX. J Biol Chem 1993; 268: 3438-3443
- 17 Yagi M, Edelhoff S, Disteche CM, Roth GJ. Structural characterization and chromosomal location of the gene encoding human platelet glycoprotein Ibβ. J Biol Chem 1994; 269: 17424-17427
- 18 Yagi M, Edelhoff S, Disteche CM, Roth GJ. Human platelet glycoproteins V and IX: Mapping of two leucine-rich glycoprotein genes to chromosome 3 and analysis of structures. Biochemistry 1995; 34: 16132-16137
- 19 Lopez JA, Leung B, Reynolds CC, Li CQ, Fox JEB. Efficient plasma membrane expression of a functional platelet glycoprotein Ib-IX complex requires the presence of its three subunits. J Biol Chem 1992; 267: 12851-12859
- 20 Calverley DC, Yagi M, Stray SM, Roth GJ. Human platelet glycoprotein V: Its role in enhancing expression of the glycoprotein lb receptor. Blood 1995; 86: 1361-1367
- 21 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: 800-809
- 22 Drouin J, McGregor JL, Parmentier S, Izaguirre CA, Clemetson KJ. Residual amounts of glycoprotein lb concomitant with near absence of glycoprotein IX in platelets of Bernard-Soulier patients. Blood 1988; 72: 1086-1093
- 23 Simsek S, Admiraal LG, Modderman PW, van der Schoot CE, von dem Borne AEGKr. Identification of a homozygous single base pair deletion in the gene coding for the human platelet glycoprotein Ibβ causing Bernard-Soulier syndrome. Thromb Haemost 1994; 72: 444-449
- 24 Ware J, Russell SR, Vicente V, Scharf RE, Tomer A, McMillan R, Ruggeri ZM. Nonsense mutation in the glycoprotein Ibα coding sequence associated with Bernard-Soulier syndrome. Proc Natl Acad Sci USA 1990; 87: 2026-2030
- 25 Kunishima S, Miura H, Fukutani H, Yoshida H, Osumi K, Kobayashi S, Ohno R, Naoe T. Bernard-Soulier syndrome Kagoshima: Ser444-stop mutation of glycoprotein (GP) Ibalpha resulting in circulating truncated GPIba and surface expression of GPIbb and GPIX. Blood 1994; 84: 3356-3362
- 26 Miller JL, Lyle VA, Cunningham D. Mutation of leucine-57 to phenylalanine in a platelet glycoprotein Ibα leucine tandem repeat occurring in patients with an autosomal dominant variant of Bernard-Soulier disease. Blood 1992; 79: 439-446
- 27 Furihata K, Yamamoto N, Yan J, Hasegawa Y, Nagasawa T, Tanoue K. An amino acid substitution of Phe for Leu 126 in a leucine-rich repeat of GPIbα associated with a variant form of Bernard-Soulier syndrome. Blood 1994; 84: 476a (abstr.)
- 28 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 Ibα. Blood 1995; 86: 3805-3814
- 29 Ware J, Russell SR, Marchese P, Murata M, Mazzucato M, De Marco L, Ruggeri ZM. Point mutation in a leucine-rich repeat of platelet glycoprotein Ibα resulting in the Bernard-Soulier syndrome. J Clin Invest 1993; 92: 1213-1220
- 30 de la Salle C, Baas MJ, Lanza F, Schwartz A, Hanau D, Chevalier J, Gachet C, Briquel ME, Cazenave JP. A three-base deletion removing a leucine residue in a leucine-rich repeat of platelet glycoprotein Iba associated with a variant of Bernard-Soulier syndrome (Nancy I). Brit J Haem 1995; 89: 386-396
- 31 Simsek S, Noris P, Lozano M, Pico M, von dem Borne AEGKr, Ribera A, Gallardo D. Cys 209 Ser mutation in the platelet membrane glycoprotein Iba gene is associated with Bernard-Soulier syndrome. Brit J Haematol 1994; 88: 839-844
- 32 Ludlow LB, Driscoll DA, Budarf ML, Konkle BA. Identification of a mutation in the promoter region of the gene encoding platelet glycoprotein Ibb resulting in the Bernard-Soulier syndrome. Blood 1995; 86 (Suppl. 01) 82a (abstr.)
- 33 Noda M, Takafuta T, Shimomura T, Fujimoto T, Yamamoto M, Tanoue K, Suehiro K, Kakishita E, Fujimura K, Kuramoto A. Nonsense mutation in the glycoprotein IX coding sequence associated with Bernard-Soulier syndrome. Blood 1994; 84: 472a (abstr.)
- 34 Wright SD, Michaelides K, Johnson DJD, West NC, Tuddenham EGD. Double heterozygosity for mutations in the platelet glycoprotein IX gene in three siblings with Bernard-Soulier syndrome. Blood 1993; 81: 2339-2347
- 35 Clemetson JM, Kyrle PA, Brenner B, Clemetson KJ. Variant Bernard-Soulier syndrome associated with a homozygous mutation in the leucine rich domain of glycoprotein IX. Blood 1994; 84: 1124-1131
- 36 Noris P, Simsek S, Stibbe J, von dem Borne AEGKr. A homozygous point mutation in a leucine-rich motif of platelet glycoprotein IX associated with Bernard-Soulier syndrome (BSS). Blood 1994; 84: 320a (abstr.)
- 37 Patarroyo M, Beatty PG, Nilsson K, Gahmberg CG. Identification of a cell-surface glycoprotein mediating cell adhesion in EBV-immortalized normal B cells. Int J Cancer 1986; 38: 539-546
- 38 Maniatis T, Fritsch EF, Sambrook J. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor NY: Cold Spring Harbor Laboratory; 1982
- 39 Saiki PK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988; 239: 487-490
- 40 Write MB, Carvalho M, Derse D, O’Brien SJ, Dean M. Detecting single base substitutions as heteroduplex polymorphisms. Genomics 1992; 12: 301-307
- 41 Soto D, Sukumar S. Improved detection of mutations in the P53 gene in human tumors as single-stranded conformation polymorphs and double-stranded heteroduplex DNA. PCR Methods and Applications 1992; 2: 96-104
- 42 Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain terminating inhibitors. Proc Natl Acad Sci USA 1977; 74: 5463-5467
- 43 Russell SD, Roth GJ. Pseudo-von Willebrand disease: A mutation in the platelet glycoprotein Iba gene associated with a hyperactive surface receptor. Blood 1993; 81: 1787-1791
- 44 Staatz WD, Rajpara SM, Wayner EA, Carter WG, Santoro SA. The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg++-dependent adhesion of platelets to collagen. J Cell Biol 1989; 108: 1917-1924