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

Kunishima, Shinji; Naoe, Tomoki; Kamiya, Tadashi; Saito, Hidehiko

doi:10.1002/ajh.10000

Cited by 38 publications

(42 citation statements)

References 26 publications

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“…Several of the GP Ib␤ gene mutations that have been described are missense mutations. 23,[28][29][30] In general, these mutations might be expected to have a minimal effect on transcript stability. However, in the case of Watanabe et al, 8 who observed abnormal vesicles, the mutation is a 13-bp deletion within the signal peptide coding region of the GP Ib␤ gene.…”

Section: Discussionmentioning

confidence: 99%

Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Kato

Martínez

Russell

et al. 2004

Blood

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Here we report the characterization of a mouse model of the Bernard-Soulier syndrome generated by a targeted disruption of the gene encoding the glycoprotein (GP) Ib␤ subunit of the GP Ib-IX complex. Similar to a Bernard-Soulier model generated by disruption of the mouse GP Ib␣ subunit, GP Ib␤ Null mice display macrothrombocytopenia and a severe bleeding phenotype. When examined by transmission electron microscopy, the large platelets produced by a GP Ib␤ Null genotype revealed ␣-granules with increased size as compared with the ␣-granules from control mouse platelets. Data are presented linking the overexpression of a septin protein, SEPT5, to the presence of larger ␣-granules in the GP Ib␤ Null platelet. The SEPT5 gene resides approximately 250 nucleotides 5 to the GP Ib␤ gene and has been associated with modulating exocytosis from neurons and platelets as part of a presynaptic protein complex. Fusion mRNA transcripts present in megakaryocytes can contain both the SEPT5 and GP Ib␤ coding sequences as a result in an imperfect polyadenylation signal within the 3 end of both the human and mouse SEPT5 genes. We observed a 2-to 3-fold increase in SEPT5 protein levels in platelets from GP Ib␤ Null mice. These results implicate SEPT5 levels in the maintenance of normal ␣-granule size and may explain the variant granules associated with human GP Ib␤ mutations and the Bernard-Soulier syndrome.

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Section: Discussionmentioning

confidence: 99%

Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Kato

Martínez

Russell

et al. 2004

Blood

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“…The symptomatic patients were homozygotes, because they had a deletion of one chromosome containing the GpIbb gene and a mutation in the other. Furthermore, BSS associated with the defective beta subunit of GpIb (BSS type B) has been reported in 22q11.2-deleted patients [4][5][6] and in homozygotes and heterozygotes for missense or non-sense mutations in GPIbb [8][9][10][11][12].…”

Section: R P a L L O T T A * V E V A N G E L I S T A M M A mentioning

confidence: 99%

Macrothrombocytopenia in velocardiofacial syndrome

Pallotta

Evangelista

Margaglione

et al. 2005

Journal of Thrombosis and Haemostasis

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crystallographic 3-D structure of the fibrinogen c chain shows that the change occurs in an outer region of the molecule ( Fig. 1), distant from the two calcium-binding sites of the c chain which are located within the amino acid sequence defined by residues 311-336 [4]. Moreover, the mutated amino acid does not lie within the regions involved in D-E contact sites [5]. Taken together, these observations suggest that altered fibrin polymerization of fibrinogen Vicenza might not be associated with a direct effect on the sites of interaction with normal adjacent monomers, but might possibly result from long-distance conformational changes induced by the mutation.

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“…Interestingly, microdeletions within chromosome 22q11 which result in the loss of one GPIBB allele (velocardiofacial syndrome) reduce the surface expression of GPIb/IX/V by 50%; however, in most cases, these mutations do not induce thrombocytopenia or platelet macrocytosis. 19 Thus, 50% expression of the GPIb/IX/V complex appears to be sufficient for 20 result in the production of larger platelets. Not enough data are presently available to unravel the molecular mechanisms that underlie these differences, and further studies on the transcription and translation of mutated genes, as well as on the processes that regulate the assembly of the GPIb/IX/V complex, are required to fully understand the pathogenesis of BSS.…”

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confidence: 99%

Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIb (Bolzano mutation)

Noris¹,

Perrotta²,

Bottega³

et al. 2011

Haematologica

119

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BackgroundBernard-Soulier syndrome is a very rare form of inherited thrombocytopenia that derives from mutations in GPIbα, GPIbb, or GPIX and is typically inherited as a recessive disease. However, some years ago it was shown that the monoallelic c.515C>T transition in the GPIBA gene (Bolzano mutation) was responsible for macrothrombocytopenia in a few Italian patients. Design and MethodsOver the past 10 years, we have searched for the Bolzano mutation in all subjects referred to our institutions because of an autosomal, dominant form of thrombocytopenia of unknown origin. ResultsWe identified 42 new Italian families (103 cases) with a thrombocytopenia induced by monoallelic Bolzano mutation. Analyses of the geographic origin of affected pedigrees and haplotypes indicated that this mutation originated in southern Italy. Although the clinical expression was variable, patients with this mutation typically had a mild form of Bernard-Soulier syndrome with mild thrombocytopenia and bleeding tendency. The most indicative laboratory findings were enlarged platelets and reduced GPIb/IX/V platelet expression; in vitro platelet aggregation was normal in nearly all of the cases. ConclusionsOur study indicates that monoallelic Bolzano mutation is the most frequent cause of inherited thrombocytopenia in Italy, affecting 20% of patients recruited at our institutions during the last 10 years. Because many people from southern Italy have emigrated during the last century, this mutation may have spread to other countries.Key words: inherited thrombocytopenia, Bolzano mutation, monoallelic, Bernard-Soulier syndrome Citation: Noris P, Perrotta S, Bottega R, Pecci A, Melazzini F, Civaschi E, Russo S, Magrin S, Loffredo G, Di Salvo V, Russo G, Casale M, De Rocco D, Grignani C, Cattaneo M, Baronci C, Dragani A, Albano V, Jankovic M, Scianguetta S, Savoia A, and Balduini CL. Clinical and laboratory

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

Cited by 38 publications

References 26 publications

Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Macrothrombocytopenia in velocardiofacial syndrome

Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIb (Bolzano mutation)

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