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.

Clemetson, K. J.; McGregor, John L.; James, Elizabeth; Dechavanne, M; Lüscher, E. F.

doi:10.1172/jci110618

Cited by 248 publications

(98 citation statements)

References 28 publications

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“…In Bernard-Soulier syndrome the platelets manifest a diminished or abolished expression of the GPIb-IX-V complex (Nurden & Caen, 1975;Clemetson et al, 1982). Recently, several gene mutations affecting either GPIba or GPIX have been shown to be associated with Bernard-Soulier syndrome.…”

Section: Discussionmentioning

confidence: 99%

Bernard‐Soulier syndrome Karlstad: Trp 498→Stop mutation resulting in a truncated glycoprotein Ibα that contains part of the transmembranous domain

et al. 1997

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Summary. In Bernard-Soulier syndrome, a hereditary bleeding disorder, the platelets are deficient in the glycoprotein (GP) Ib-IX-V complex, a major receptor for the von Willebrand factor. The components of the complex are encoded by separate genes. Patients with this syndrome have a variable expression level of the receptor protein on platelets depending on the specific genetic abnormality. We describe a patient with life-long bleeding symptoms, who is homozygous for a unique stop mutation, Trp 498 → Stop in the GPIba gene, resulting in a truncated GPIba polypeptide chain. In contrast to previously reported truncated forms of GPIba, this form contains a portion of the transmembranous domain as well as the juxtamembranous cysteines engaged in a disulphide bond with GPIbb. Flow cytometry with GPIba antibodies demonstrated the presence of GPIb on the patient's platelets, although in reduced amounts compared to normal controls. GPIX was similarly detectable. Immunoblotting demonstrated that the patient synthesized a truncated GPIba of the expected size of 130 K, which was, however, sensitive to proteolysis. These studies show that GPIba lacking the intracytoplasmic tail can be expressed at the platelet surface provided elements of the transmembranous domain are present.

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Section: Discussionmentioning

confidence: 99%

Bernard‐Soulier syndrome Karlstad: Trp 498→Stop mutation resulting in a truncated glycoprotein Ibα that contains part of the transmembranous domain

et al. 1997

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“…It is characterized by the absence of a major carbohydrate-containing protein complex on the platelet surface 2 which results in a severe deficiency of four glycoproteins (GP): GPIbα, GPIbb, GPIX, and GPV. 3,4 These polypeptides associate in the ratio 2:2:2:1 on the platelet membrane to form the GPIb/IX/V complex which is assembled in the endoplasmic reticulum and the Golgi apparatus before localizing on the surface. 5,6 The presence of GPIb/IX/V is essential for hemostasis, as the extracellular domain of GPIbα binds to the subendothelial von Willebrand factor that is exposed at vascular injury sites.…”

Section: Introductionmentioning

confidence: 99%

Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations

Savoia¹,

Pastore²,

Rocco³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundBernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center. Design and MethodsThirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses. ResultsPatients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies. ConclusionsRegardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.Key words: Bernard-Soulier syndrome, macrothrombocytopenia, GP1BA, GP1BB and GP9 mutations. Citation: Savoia

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“…The Bernard-Soulier syndrome is character-*Address correspondence to this author at the "Hygeia" Diagnostic & Therapeutic Centre. 9 Erythrou Stavrou St. 151 23 Athens, Greece; Tel: +30-210-6867311; Fax: +30-210-6867299; E-mail: zpanos@otenet.gr ized by bleeding diathesis, thrombocytopenia with giant platelets, no response to ristocetin-induced aggregation and lack of the receptor [17]. Finally the GpIa/IIa complex (CD49b/CD29) (collagen receptor) facilitates collagen adhesion and is being expressed in various cell subtypes, with 1000 molecules present on the platelet surface [18].…”

Section: Antigenic Targetsmentioning

confidence: 99%

SLE Thrombocytopenia: From Peripheral Platelet Destruction to Central Hemopoietic Defect

Ziakas¹

2008

TOHJ

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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.

Cited by 248 publications

References 28 publications

Bernard‐Soulier syndrome Karlstad: Trp 498→Stop mutation resulting in a truncated glycoprotein Ibα that contains part of the transmembranous domain

Bernard‐Soulier syndrome Karlstad: Trp 498→Stop mutation resulting in a truncated glycoprotein Ibα that contains part of the transmembranous domain

Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations

SLE Thrombocytopenia: From Peripheral Platelet Destruction to Central Hemopoietic Defect

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