Point mutation in a leucine-rich repeat of platelet glycoprotein Ib alpha resulting in the Bernard-Soulier syndrome.

Ware, Jerry; Russell, Susan; Marchese, Patrizia; Murata, Mitsuru; Mazzucato, M.; Marco, Luigi De; Ruggeri, Zaverio M.

doi:10.1172/jci116692

Cited by 133 publications

(104 citation statements)

References 42 publications

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“…To confirm the diagnosis, we performed GPIb mutation screen. We found the heterozygous, C515T or A156V mutation (Figure 2(b)) and confirmed the diagnosis of autosomal dominant or Bolzano-type BSS in this patient/family [4,6]. BSS is a rare inherited platelet disorder, characterized by variable thrombocytopenia and large defective platelets.…”

supporting

confidence: 78%

A family with bolzano-type Bernard–Soulier syndrome carries a benign A1939T MYH9 mutation

Sarangi

Golightly

Weber³

et al. 2012

Platelets

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supporting

confidence: 78%

A family with bolzano-type Bernard–Soulier syndrome carries a benign A1939T MYH9 mutation

Sarangi

Golightly

Weber³

et al. 2012

Platelets

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“…Nonsense mutations of the GPIba gene leading to a truncated GPIba polypeptide generally resulted in undetectable surface GPIb, whereas small amounts of GPIX and GPV were still present (Ware et al, 1990;Simsek et al, 1994a;Kunishima et al, 1994;Noda et al, 1995). Missense mutations leading to amino acid substitution or deletion in GPIba showed a better preservation of receptor protein, although functionally defective (Miller et al, 1992;Ware et al, 1993;de la Salle et al, 1995;Li et al, 1995). Mutations of the GPIX gene were shown to result in practically abolished expression of GPIX but some preservation of GPIb and GPV could be observed (Wright et al, 1993;Clemetson et al, 1994;Noda et al, 1995).…”

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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“…2 Alternatively, high molecular weight human VWF may display enhanced binding to the platelet GpIb␣/IX/V receptor in rats and dogs but not in mice. Indeed, it has been reported that human VWF is not recognized by murine GpIb␣ (41). This multimerization-independent sur-2 C. V. Denis, unpublished observation.…”

Section: Table II Affinity Constants For the Interactions Between Vwfmentioning

confidence: 94%

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

Lenting

Westein

Terraube

et al. 2004

Journal of Biological Chemistry

136

189

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To explore the molecular basis of von Willebrand factor (VWF) clearance, an experimental model employing VWF-deficient mice was developed. Biodistribution was examined by the injection of radiolabeled VWF, which was primarily directed to the liver with minor amounts in other organs. Disappearance of VWF from plasma was characterized by a rapid initial phase (t1 ⁄2 ␣ ‫؍‬ 13 min) and a slow secondary phase (t1 ⁄2 ␤ ‫؍‬ 3 h), with a mean residence time (MRT) of 2.8 h. A similar clearance was observed for VWF consisting of only high or low molecular weight multimers, indicating that, in our experimental model, clearance is independent of multimeric distribution. This allowed us to compare the survival of fulllength VWF to truncated variants. Deletion of both the amino-terminal D -D3 and carboxyl-terminal D4-CK domains resulted in a fragment with a similar clearance to wild-type VWF. Deletion of only the D -D3 region was associated with an almost 2-fold lower recovery and increased clearance (MRT ‫؍‬ 1.6 h), whereas deletion of only the D4-CK region resulted in a significantly reduced clearance (MRT ‫؍‬ 4.5 h, p < 0.02). These results point to a role of the D -D3 region in preventing clearance of VWF. Furthermore, replacement of D3 domain residue Arg-1205 by His resulted in a markedly increased clearance (MRT ‫؍‬ 0.3 h; p ‫؍‬ 0.004). Therefore, this mutation seems to abrogate the protective effect of the D -D3 region. In vitro analysis of this mutant also revealed a 2-fold reduced affinity for VWF propeptide at low pH, showing that mutation of Arg-1205 results not only in an increased clearance rate but is also associated with an impaired pH-dependent interaction with VWF propeptide.von Willebrand factor (VWF) 1 is a multimeric plasma protein that participates in the hemostatic process. The absence of functional VWF is associated with an abnormal bleeding tendency known as von Willebrand Disease (VWD) (1, 2). VWF contributes to hemostasis in a dual manner. First, it promotes the adhesion of platelets at sites of vascular injury by acting as a molecular bridge between the sub-endothelial collagen matrix and the platelet-surface receptor complex glycoprotein (Gp) Ib␣/IX/V (3). In addition, VWF serves as a carrier protein for coagulation factor VIII (FVIII) in the circulation. This chaperone function results in stabilization of the FVIII heterodimeric structure (4) and protection of FVIII from premature clearance by the low density lipoprotein receptor-related protein (5, 6).VWF is produced and stored in endothelial cells and megakaryocytes. It is synthesized as pre-pro-VWF, a single chain polypeptide with the domain structure

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Point mutation in a leucine-rich repeat of platelet glycoprotein Ib alpha resulting in the Bernard-Soulier syndrome.

Cited by 133 publications

References 42 publications

A family with bolzano-type Bernard–Soulier syndrome carries a benign A1939T MYH9 mutation

A family with bolzano-type Bernard–Soulier syndrome carries a benign A1939T MYH9 mutation

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

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

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