Homozygous Pro74 → Arg Mutation in the Platelet Glycoprotein Ibβ Gene Associated with Bernard-Soulier Syndrome

Kunishima, Shinji; Tomiyama, Yoshiaki; Honda, Susumu; Fukunishi, Mariko; Hara, Junichi; Inoue, Chihiro; Kamiya, Tadashi; Saito, Hidehiko

doi:10.1055/s-0037-1613977

Thromb Haemost

2000

DOI: 10.1055/s-0037-1613977

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Homozygous Pro74 → Arg Mutation in the Platelet Glycoprotein Ibβ Gene Associated with Bernard-Soulier Syndrome

Shinji Kunishima¹,

Yoshiaki Tomiyama²,

Susumu Honda³

et al.

Abstract: SummaryBernard-Soulier syndrome (BSS) is an autosomal recessive bleeding disorder due to quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V complex, the platelet receptor for von Willebrand factor. This complex is composed of four subunits, GPIbα, GPIbβ, GPIX and GPV. We describe here the genetic basis of the disorder in a patient with BSS. Flow cytometric analysis of the patient’s platelets showed greatly reduced GPIbα and GPIX surface expression. Immunoblot analysis disclosed absence … Show more

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Cited by 22 publications

References 27 publications

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Novel heterozygous missense mutation in the platelet glycoprotein Ibβ gene associated with isolated giant platelet disorder

et al. 2001

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The glycoprotein (GP) Ib/IX/V complex plays an important role in primary hemostasis, serving as the platelet receptor for von Willebrand factor (vWF). Recent studies have shown that the phenotype caused by mutations in the subunits of the GPIb/IX complex spans a wide spectrum; from the normal phenotype, to isolated giant platelet disorders (GPD), and to the full-blown bleeding disorder, the Bernard-Soulier syndrome (BSS). We characterize here a novel missense mutation of the GPIbb gene associated with isolated GPD. In the patient's platelets, the expression level of the GPIb/IX complex was moderately reduced compared with that of the GPIIb/IIIa complex, whereas the latter was expressed at higher levels than in a normal control. Immunoblot analysis showed normal electrophoretic mobility of GPIba, GPIbb, and GPIX. However, the amount of GPIbb was approximately 66% of the normal value. DNA sequencing analysis revealed a novel heterozygous missense mutation in the GPIbb gene that converts Arg (CGC) to Cys (TGC) at residue 17. Transient transfection studies demonstrated that mutant GPIbb protein was not detected in transfected 293T cells. These ®ndings indicated that null expression of the abnormal GPIbb causes decreased expression of the complex and results in the GPD phenotype in the patient, and suggested that homozygosity of the mutation may lead to a

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Novel heterozygous missense mutation in the platelet glycoprotein Ibβ gene associated with isolated giant platelet disorder

et al. 2001

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Novel nonsense mutation in the platelet glycoprotein Ibβ gene associated with Bernard‐Soulier syndrome

Kunishima

Matsushita

Ito³

et al. 2002

American J Hematol

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Bernard-Soulier syndrome (BSS) is an autosomal recessive bleeding disorder caused by quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V complex, the platelet receptor for von Willebrand factor. This complex is composed of four subunits, GPIb␣, GPIb␤, GPIX, and GPV, and the coordinated assembly of GPIb␣, GPIb␤, and GPIX is required for the efficient surface expression of a functional complex. We report here a novel nonsense mutation of the GPIb␤ gene associated with BSS. Flow cytometric analysis of the patient's platelets showed markedly reduced GPIb␣ and absent GPIX surface expression. Immunoblot analysis of solubilized platelets showed that a small amount of GPIb␣ was detected; however, GPIb␤ and GPIX were undetectable. DNA sequencing analysis revealed a novel nonsense mutation of the GPIb␤ gene that converts Trp (

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Spectrum of the Mutations in Bernard-Soulier Syndrome

et al. 2014

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Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

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Homozygous Pro74 → Arg Mutation in the Platelet Glycoprotein Ibβ Gene Associated with Bernard-Soulier Syndrome

Cited by 22 publications

References 27 publications

Novel heterozygous missense mutation in the platelet glycoprotein Ibβ gene associated with isolated giant platelet disorder

Novel heterozygous missense mutation in the platelet glycoprotein Ibβ gene associated with isolated giant platelet disorder

Novel nonsense mutation in the platelet glycoprotein Ibβ gene associated with Bernard‐Soulier syndrome

Spectrum of the Mutations in Bernard-Soulier Syndrome

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