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Other entities represented in this entry:
SNOMEDCT: 234478007, 54569005; ORPHA: 274; DO: 2217;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q21.3 | Bernard-Soulier syndrome, type C | 231200 | Autosomal recessive | 3 | GP9 | 173515 |
| 17p13.2 | Bernard-Soulier syndrome, type A1 (recessive) | 231200 | Autosomal recessive | 3 | GP1BA | 606672 |
| 22q11.21 | Giant platelet disorder, isolated | 231200 | Autosomal recessive | 3 | GP1BB | 138720 |
| 22q11.21 | Bernard-Soulier syndrome, type B | 231200 | Autosomal recessive | 3 | GP1BB | 138720 |
A number sign (#) is used with this entry because Bernard-Soulier syndrome (BSS) has been found to be caused by mutation in the GP1BA gene (606672), the GP1BB gene (138720), or the GP9 gene (173515); the forms of BSS caused by homozygous or compound heterozygous mutation in these genes are here referred to as types A1, B, and C, respectively.
See also autosomal dominant Bernard-Soulier syndrome (BSSA2; 153670), which can be caused by heterozygous mutation in the GP1BA gene. It is much less common than autosomal recessive Bernard-Soulier syndrome.
Bernard-Soulier syndrome is an autosomal recessive bleeding disorder caused by a defect in or deficiency of the platelet membrane von Willebrand factor (VWF; 613160) receptor complex, glycoprotein Ib (GP Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA, GP1BB, GP9, and GP5 (173511).
Genetic Heterogeneity of Platelet-Type Bleeding Disorders
Inherited platelet disorders are a heterogeneous group of bleeding disorders affecting platelet number, function, or both. Functional defects can involve platelet receptors, signaling pathways, cytoskeletal proteins, granule contents, activation, or aggregation (review by Cox et al., 2011 and Nurden and Nurden, 2011).
Platelet-type bleeding disorders include Bernard-Soulier syndrome (BDPLT1); Glanzmann thrombasthenia (BDPLT2; 273800), caused by mutation in the ITGA2B (607759) or ITGB3 (173470) gene; pseudo-von Willebrand disease (BDPLT3; 177820), caused by mutation in the GP1BA gene (606672); gray platelet syndrome (BDPLT4; 139090), caused by mutation in the NBEAL2 gene (614169); Quebec platelet disorder (BDPLT5; 601709), caused by tandem duplication of the PLAU gene (191840); May-Hegglin anomaly (BDPLT6; 155100), caused by mutation in the MYH9 gene (160775); Scott syndrome (BDPLT7; 262890), caused by mutation in the TMEM16F gene (608663); BDPLT8 (609821), caused by mutation in the P2RY12 gene (600515); BDPLT9 (614200), associated with deficiency of the glycoprotein Ia/IIa receptor (see ITGA2; 192974); glycoprotein IV deficiency (BDPLT10; 608404), caused by mutation in the CD36 gene (173510); BDPLT11 (614201), caused by mutation in the GP6 gene (605546); BDPLT12 (605735), associated with a deficiency of platelet COX1 (176805); susceptibility to BDPLT13 (614009), caused by mutation in the TBXA2R gene (188070); BDPLT14 (614158), associated with deficiency of thromboxane synthetase (TBXAS1; 274180); BDPLT15 (615193), caused by mutation in the ACTN1 gene (102575); BDPLT16 (187800), caused by mutation in the ITGA2B (607759) or ITGB3 (173470) gene; BDPLT17 (187900), caused by mutation in the GFI1B gene (604383); BDPLT18 (615888), caused by mutation in the RASGRP2 gene (605577); BDPLT19 (616176), caused by mutation in the PRKACG gene (176893); BDPLT20 (616913), caused by mutation in the SLFN14 gene (614958); BDPLT21 (617443), caused by mutation in the FLI1 gene (193067); BDPLT22 (618462), caused by mutation in the EPHB2 gene (600997); BDPLT23 (619267), caused by mutation in the ITGB3 gene (173470); BDPLT24 (619271), caused by mutation in the ITGB3 gene (173470); and BDPLT25 (620486), caused by mutation in the TPM4 gene (600317).
See reviews by Rao (2003), Cox et al. (2011), and Nurden and Nurden (2011).
For a discussion of the genetic heterogeneity of hereditary thrombocytopenia, see THC1 (313900).
Bernard-Soulier syndrome and other platelet disorders have some similar clinical features, including mucosal bleeding, purpuric skin bleeding, epistaxis, and menorrhagia. In BSS, bleeding time is prolonged (in some cases longer than 20 minutes), platelets are large, and there is no platelet aggregation in response to ristocetin or addition of von Willebrand factor. Thrombocytopenia may or may not be present (Lopez et al., 1998).
Bernard and Soulier (1948) described a congenital bleeding disorder in patients who had unusually large platelets and a moderate degree of thrombocytopenia. All had a markedly prolonged bleeding time. The same abnormality was described in a family by Kanska et al. (1963). Cullum et al. (1967) described 2 brothers from a consanguineous family of Sicilian origin with a bleeding disorder characterized by thrombocytopenia, abnormally large platelets, prolonged bleeding time, low platelet thromboplastic activity, and normal clotting retraction. All 5 of the brothers' children had abnormal platelet morphology. Multiple other members of the extended family had abnormal platelets without the full bleeding disorder. The authors concluded that the 2 affected brothers were homozygous and the other members with isolated abnormal platelet morphology were heterozygotes. The phospholipid content of platelets was increased. Cullum et al. (1967) suggested that abnormally rapid removal of the bizarre platelets may be responsible for thrombocytopenia. Weiss et al. (1974) studied 2 black first cousins with the disorder.
In the case of a Swedish patient with Bernard-Soulier syndrome, Waldenstrom et al. (1991) found that the parents had common ancestors in the 17th century. In this and another patient, bleeding time was shortened by infusion of dDAVP (1-deamino-8D-arginine vasopressin), although it was not completely normalized.
Grottum and Solum (1969) found reduced electrophoretic mobility of BSS platelets due to a marked decrease in the concentration of sialic acid on their membranes.
Weiss et al. (1974) noted that the adhesion of BSS platelets to rabbit aortic subendothelium was impaired. The authors suggested that there may be a reduced or abnormal glycoprotein involved, and they presented evidence suggesting that platelets in this syndrome lack a receptor for the von Willebrand factor.
In 2 patients with the Bernard-Soulier syndrome, Nurden and Caen (1975) were unable to find more than traces of a 155,000 molecular mass glycoprotein in membrane fraction from platelets. Previously reported findings of sialic acid content and reduced electrophoretic mobility of Bernard-Soulier platelets were consistent. Caen et al. (1976) confirmed a defect in BSS platelet adhesion to rabbit aorta subendothelium. The factor VIII-von Willebrand protein was apparently normal on Bernard-Soulier platelets when studied by an immuno-electron-microscopic technique; however, a reduced content of a major platelet glycoprotein was found by two methods.
In 3 patients with the Bernard-Soulier syndrome, Kunicki et al. (1978) could not detect the platelet membrane receptor for quinidine and quinine-dependent antibodies. The platelets were likewise deficient in glycoproteins Ib and Is. In normal platelets, apparently, complete cleavage of the glycoproteins had little effect on antibody receptor activity, suggesting the presence of a second membrane defect in BSS.
Hagen et al. (1980) stated that there was clear evidence that there is a defect in von Willebrand receptor in the Bernard-Soulier syndrome (see also Moake et al., 1980), and that the normal receptor is glycoprotein I (Nurden and Caen, 1975). Heterozygotes (e.g., parents) have a decrease in glycoprotein I but no impairment of platelet function and no abnormal bleeding.
Montgomery et al. (1983) demonstrated that an assay using monoclonal antibodies raised in the mouse can recognize the deficiency of glycoprotein Ib in the Bernard-Soulier syndrome and of the glycoprotein IIb/IIIa in Glanzmann thrombasthenia (GTA; 273800).
Stricker et al. (1985) described acquired Bernard-Soulier syndrome in a patient with a lymphoproliferative disorder. They demonstrated an IgG antibody that inhibited aggregation of normal platelets by ristocetin and by von Willebrand factor. By Western blotting, they found that the antibody bound specifically to an antigen of MW 210,000 present in normal platelets but missing in BSS platelets.
In a patient with autosomal recessive Bernard-Soulier syndrome, Ware et al. (1990) identified a homozygous nonsense mutation in the GP1BA gene (606672.0001), which encodes the alpha chain of the GP Ib receptor.
By RFLP analysis, Finch et al. (1990) ruled out the GP1BA gene as the site of the mutation in a BSS family with 2 affected sibs. The authors suggested that the cause of BSS in this family was due to other genes encoding platelet membrane glycoproteins, including GP1BB, GP IX, and possibly GP V, which may result in failure of assembly and cell surface expression of the von Willebrand factor receptor complex. This suggestion came from the observation that other membrane complexes such as platelet GP IIb-IIIa (273800, 173470) and the T-cell receptor/CD3 complex (186790, 186830, 186740) require coordinate expression of multiple subunits for normal receptor assembly.
In a male patient with the velocardiofacial syndrome caused by a deletion in chromosome 22q and symptoms of BSS, Ludlow et al. (1996) identified a mutation in the upstream promoter of the GP1BB gene (138720.0003). Thus, in this patient, BSS resulted from deletion of 1 copy of the gene and mutation in the other copy.
In a family with BSS, Wright et al. (1993) identified compound heterozygous mutations in the GP9 gene (173515.0001, 173515.0002). The authors suggested that abnormal GP IX prevented stable assembly of the GP Ib complex.
Noda et al. (1995) reported 2 BSS patients: one had a mutation in the GP9 gene and the other had a mutation in the GP1BA gene. They noted that abnormality of a single component of the receptor complex resulted in heterogeneous surface expression of all the components.
In 2 Japanese sisters with giant platelets, mild childhood bleeding, and impaired ristocetin aggregation, Kunishima et al. (1997) identified compound heterozygosity for mutations in the GP1BB gene (138720.0001-138720.0002). The authors suggested that the phenotype caused by mutations in the subunits of the GP Ib complex could span the spectrum from a normal phenotype, to isolated giant platelet disorder, to full-blown Bernard-Soulier syndrome.
Ware et al. (2000) disrupted the Gp1ba gene of the mouse and described a murine model recapitulating the hallmark characteristics of human Bernard-Soulier syndrome. Using transgenic technology, they rescued the murine BSS phenotype by expression of the human glycoprotein Ib-alpha subunit on the surface of circulating mouse platelets.
Kato et al. (2004) found that Gp1bb-null mice had macrothrombocytopenia and a severe bleeding phenotype. Electron microscopy showed increased size of the alpha-granules compared to control alpha-granules, possibly resulting from disruption of the neighboring Sept5 gene (602724), approximately 250 nucleotides 5-prime to the Gp1bb gene. Sept5 protein levels in platelets from Gp1bb-null mice were 2- to 3-fold increased compared to controls.
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