G→A transition at nucleotide 2110 in the human platelet glycoprotein (GP) IX gene resulting in ALA139(ACC)→THR(GCC) substitution

Hayashi, Tomohiro; Suzuki, Keijiroh; Akiba, Jiro; Yahagi, Akito; Tajima, Katsushi; Satoh, Shuichi; Sasaki, Hideo

doi:10.1007/bf02766961

Cited by 7 publications

(5 citation statements)

References 8 publications

(1 reference statement)

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“…The A140T mutation in the GPIX TM domain was first described as a polymorphism because no adverse effects on platelet number, morphology and GPIb‐IX expression were found in homozygotes [29,30]. However, it was the only mutation in the GPIb–IX complex of a BSS patient [31].…”

Section: Resultsmentioning

confidence: 99%

Role of the transmembrane domain of glycoprotein IX in assembly of the glycoprotein Ib–IX complex

Luo

López

et al. 2007

Journal of Thrombosis and Haemostasis

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Summary. Background: The glycoprotein (GP) Ib-IX complex is critically involved in platelet adhesion to von Willebrand factor and in the initial step of platelet activation. How this complex is assembled is not clear. We previously showed that the transmembrane (TM) domains of the GPIba and GPIbb subunits interact and participate in complex assembly. Objectives and methods: Here, we have investigated the role of the TM and cytoplasmic domains of GPIX in assembly of the GPIb-IX complex, by analyzing the mutational effects on complex expression and assembly in transiently transfected Chinese hamster ovary cells. Results: Replacing the cytoplasmic domain of GPIX with a poly-alanine sequence had little effect on surface expression and structural integrity of the GPIb-IX complex. In contrast, replacing the GPIX TM domain (residues 132-153) with a poly-leucine-alanine sequence markedly disrupted complex formation of GPIX with GPIba, interfered with GPIb formation, and decreased surface expression of the host complex. We further analyzed the contributions of a number of GPIX TM residues to complex formation by mutagenesis and found significant roles for Asp135 and several Leu residues. Conclusions: The TM domain, rather than the cytoplasmic domain, of GPIX plays an important role in expression and assembly of the GPIb-IX complex by interacting with its counterparts of GPIb. These TM domains may form a parallel four-helical bundle structure in the complex.

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Section: Resultsmentioning

confidence: 99%

Role of the transmembrane domain of glycoprotein IX in assembly of the glycoprotein Ib–IX complex

Luo

López

et al. 2007

Journal of Thrombosis and Haemostasis

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“…Allele-specific restriction analysis confirmed that the patient and the mother were heterozygous for the substitution. This substitution was recently described by Hayashi et al, as a polymorphism (18). They reported that platelets from 139Thr/Thr individuals expressed similar GPIb/IX levels to those from 139Ala/Ala individuals.…”

Section: Resultsmentioning

confidence: 54%

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

Kunishima¹,

Tomiyama²,

Honda³

et al. 2000

Thromb Haemost

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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 of GPIbα, GPIbβ and GPIX in the platelets. DNA sequencing analysis revealed a novel missense mutation in the GPIbβ gene that converts Pro (CCG) to Arg (CGG) at residue 74. Homozygosity of the mutation was confirmed by allele-specific restriction analysis, chromosome 22 microsatellite analysis and quantitative Southern blotting. The mutant GPIbβ was normally transcribed. Transient transfection studies confirmed that mutant GPIbβ impairs surface expression of GPIb/IX, showing that the mutation is responsible for a BSS phenotype observed in the patient.

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“…Such a mutation would therefore be expected to abolish proper expression of GPIb–IX in the membrane. The A140T mutation in GPIX appears to fit into this mechanism, but its effect is mild or even negligible in many cases .…”

Section: Differential Pathogenesis Of Bss Mutationsmentioning

confidence: 99%

The organizing principle of the platelet glycoprotein Ib–IX–V complex

Emsley

2013

Journal of Thrombosis and Haemostasis

137

125

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Summary The glycoprotein (GP)Ib-IX-V complex is the platelet receptor for von Willebrand factor and many other molecules critically involved in he most as is and thrombosis. The lack of functional GPIb-IX-V complexes on the platelet surface is the cause of Bernard-Soulier syndrome, a rare hereditary bleeding disorder also associated with macro thrombocytopenia. The GPIb-IX-V complex contains GPIbα, GPIbβ, GPIX and GPV subunits, all of which are type I trans membrane proteins containing leucine-rich repeat domains. Although all the subunits were identified decades ago, not until recently did the mechanism of complex assembly begin to emerge from a systematic characterization of inter-subunit interactions. This review summarizes forces driving the assembly of the GPIb-IX-V complex, discusses their implication on the pathogenesis of Bernard-Soulier syndrome, and identifies questions that remain about the structure and organization of GPIb-IX-V.

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G→A transition at nucleotide 2110 in the human platelet glycoprotein (GP) IX gene resulting in ALA139(ACC)→THR(GCC) substitution

Cited by 7 publications

References 8 publications

Role of the transmembrane domain of glycoprotein IX in assembly of the glycoprotein Ib–IX complex

Role of the transmembrane domain of glycoprotein IX in assembly of the glycoprotein Ib–IX complex

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

The organizing principle of the platelet glycoprotein Ib–IX–V complex

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