Cys209 Ser mutation in the platelet membrane glycoprotein ibα gene is associated with Bernard‐Soulier syndrome

Şimşek, Suat; Noris, Patrizia; Lozano, Miguel; Pico, M.; Borne, A. E. G. K. Von Dem; Ribera, Anna; Gallardo, Dominique

doi:10.1111/j.1365-2141.1994.tb05125.x

Cited by 58 publications

(28 citation statements)

References 23 publications

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“…GPIba or GPIbb were not detected by immunoblotting but membrane integrins were normally present. The patient has a homozygous T715A mutation in GPIBA, that results in a Cys209?Ser substitution in GPIba, previously reported in an unrelated Spanish BSS propositus [25].…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

et al. 2010

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In the Bernard-Soulier syndrome (BSS), the giant platelets are said to have increased phosphatidylserine (PS) surface exposure in the resting state and shortened survival in the circulation. When normal platelets are activated, they undergo many biochemical and morphological changes, some of which are apoptotic. Herein, we investigated apoptotic-like events in BSS platelets upon activation, specifically, PS exposure, microparticle (MP) formation, cell shrinkage, and loss of mitochondrial inner membrane potential (DC m ). Platelets from two unrelated BSS patients were examined in whole blood; agonists used were collagen, thrombin, PAR1-or PAR4-activating peptides (APs), or combinations of collagen with thrombin, and the PAR-APs. Flow cytometry was used to measure PS exposure (annexin A5 binding), platelet-derived MPs (forward scatter; events <0.75 lm size), and DC m (TMRM fluorescence). PS exposure was increased on resting and activated BSS platelets, and this was independent of the platelet size. MP formation by BSS platelets was generally enhanced. Cell shrinkage occurred on activation to form smaller, PS-exposing platelets in BSS and controls. A proportion of PS-exposing BSS and control platelets exhibited DC m loss, but unlike controls, there was also loss of DC m in the BSS platelets not exposing PS. Thus, BSS platelets undergo apoptotic-like events upon activation, with PS exposure and MP formation being enhanced. These events may play a role in the shortened survival in BSS, as well as affecting thrombin generation. Am. J. Hematol. 85:584-592, 2010. V

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Section: Patients Materials and Methodsmentioning

confidence: 99%

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

et al. 2010

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“…Substitution of the residue into a charged group would require an even higher energetic cost to bury side chain, thus destabilizing the fold of the glycoprotein. The p.Cys225Ser mutation identified in family F2 and previously reported in another 2 cases 21,22 affects the Cys225-Cys264 disulfide, leading to a strong destabilizing effect on the fold.…”

Section: Missense Mutations Are Predicted To Destabilize Protein Foldmentioning

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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“…Nine defects have hitherto been reported for the GPIba gene. These include missense (Miller et al, 1992;Ware et al, 1993;Simsek et al, 1994b;Li et al, 1995), deletion (De la Salle et al, 1995) and frameshift mutations (Simsek et al, 1994a;Noda et al, 1995) as well as stop codons resulting in a truncated protein (Ware et al, 1990;Kunishima et al, 1994;Noda et al, 1995). A few deficiencies of the GPIX gene are also on record (Wright et al, 1993;Clemetson et al, 1994;Donnér et al, 1996, Noda et al, 1996.…”

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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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Cys209 Ser mutation in the platelet membrane glycoprotein ibα gene is associated with Bernard‐Soulier syndrome

Cited by 58 publications

References 23 publications

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

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

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

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