The association of the  1-tubulin Q43P polymorphism with intracerebral hemorrhage in men

Navarro-Núñez, Leyre; Lozano, Marı́a Luisa; Rivera, José; Corral, Javier; Roldán, Vanessa; Gónzález-Conejero, Rocío; Iniesta, Juan Antonio; Montaner, Joan; Vicente, Vicente; Martı́nez, Constantino

doi:10.3324/haematol.10689

Cited by 36 publications

(34 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The former was recently described as a functional polymorphism. 8,14 The prevalence of the P43 allele was higher in patients with congenital macrothrombocytopenia (0.12) than controls (0.06). 8 We also found a similar gene frequency of 0.16 and 0.06 in our patients and controls, respectively (Table S2).…”

Section: Resultsmentioning

confidence: 99%

Mutation of the β1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly

Kunishima

Kobayashi

Itoh

et al. 2009

Blood

165

136

View full text Add to dashboard Cite

Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. We identified the first TUBB1 mutation, R318W, in a patient with congenital macrothrombocytopenia. The patient was heterozygous for Q43P, but this single-nucleotide polymorphism (SNP) did not relate to macrothrombocytopenia. Although no abnormal platelet ␤1-tubulin localization/marginal band organization was observed, the level of ␤1-tubulin was decreased by approximately 50% compared with healthy controls. Large and irregular bleb protrusions observed in megakaryocytes derived from the patient's peripheral blood CD34 ؉ cells suggested impaired megakaryocyte fragmentation and release of large platelets. In vitro transfection experiments in Chinese hamster ovary (CHO) cells demonstrated no incorporation of mutant ␤1-tubulin into microtubules, but the formation of punctuated insoluble aggregates. These results suggested that mutant protein is prone to aggregation but is unstable within megakaryocytes/platelets. Alternatively, mutant ␤1-tubulin may not be transported from the megakaryocytes into platelets. W318 ␤1-tubulin may interfere with normal platelet production, resulting in macrothrombocytopenia. IntroductionCongenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. [1][2][3] The most frequent forms include MYH9 disorders, such as May-Hegglin anomaly, and Bernard-Soulier syndrome. In approximately half of the cases the pathogenesis remains unknown; thus, a definite diagnosis is not possible. The linkage between the membrane skeleton and cytoskeletal actin filaments as well as the marginal microtubule band maintains normal platelet morphology. 4,5 Defects in these systems may result in macrothrombocytopenia. The microtubules are assembled from ␣-and ␤-tubulin heterodimers. ␤1-Tubulin expression is restricted in the megakaryocyte/platelet lineage. 6 Tubb1 knockout mice show thrombocytopenia and spherical platelets. 7 TUBB1 Q43P functional polymorphism has been reported. However, it may not be relevant to macrothrombocytopenia. 8 We identified the first TUBB1 mutation affecting microtubule assembly in congenital macrothrombocytopenia. Methods PatientThe patient was a 7-year-old boy who was incidentally found to have thrombocytopenia (platelets, 40-60 ϫ 10 9 /L). He was diagnosed with immune thrombocytopenic purpura. Peripheral blood smears showed the prominent appearance of giant platelets. Electron microscopy showed no other abnormalities ( Figure 1A,B). There were no leukocyte inclusion bodies, confirmed by myosin IIA localization. 9 The platelets aggregated normally with adenosine diphosphate (ADP), collagen, and ristocetin. Flow cytometry showed normal expression of platelet GPIb/IX. An initial bone marrow examination revealed normal megakaryocyte number and morphology. The mother of the patient also had macrothrombocytopenia. Peripheral blood samples were obtained after the mother gave informed consent in accordance with the Declaration of Helsinki for the study, which was approved by the...

show abstract

Section: Resultsmentioning

confidence: 99%

Mutation of the β1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly

Kunishima

Kobayashi

Itoh

et al. 2009

Blood

165

136

View full text Add to dashboard Cite

show abstract

“…So far, b-tubulin isotype genes have been considered highly conserved (27); however, here we prove that b-tubulin VI differentiates in this respect from the rest of isotypes and exhibits common variation in the coding region. b-tubulin VI Q43P was previously described and associated with a reduced risk of arterial thrombosis and an increased risk of intracerebral hemorrhage by modulating the platelet function and structure (9,10). In addition, a rare b-tubulin VI variant, R318W, was described in a case of congenital macrothrombocytopenia (11).…”

Section: Discussionmentioning

confidence: 99%

“…However, the hematologic isotype VI is an exception, and a common missense polymorphism (Q43P) has been associated with an altered risk of cardiovascular disease by modulating platelet function and structure (9,10). There is also a report on a rare b-tubulin VI missense variant (R318W) responsible for congenital macrothrombocytopenia (11).…”

Section: Introductionmentioning

confidence: 99%

Hematologic β-Tubulin VI Isoform Exhibits Genetic Variability That Influences Paclitaxel Toxicity

et al. 2012

View full text Add to dashboard Cite

Cellular microtubules composed of a-b-tubulin heterodimers that are essential for cell shape, division, and intracellular transport are valid targets for anticancer therapy. However, not all the conserved but differentially expressed members of the b-tubulin gene superfamily have been investigated for their role in these settings. In this study, we examined roles for the hematologic isoform b-tubulin VI and functional genetic variants in the gene. b-tubulin VI was highly expressed in blood cells with a substantial interindividual variability (seven-fold variation in mRNA). We characterized DNA missense variations leading to Q43P, T274M, and R307H, and a rare nonsense variant, Y55X. Because variations in the hematologic target of microtubule-binding drugs might alter their myelosuppressive action, we tested their effect in cell lines stably expressing the different b-tubulin VI full-length variants, finding that the T274M change significantly decreased sensitivity to paclitaxel-induced tubulin polymerization. Furthermore, patients treated with paclitaxel and carrying b-tubulin VI T274M exhibited a significantly lower thrombocytopenia than wild-type homozygous patients (P ¼ 0.031). Together, our findings define b-tubulin VI as a hematologic isotype with significant genetic variation in humans that may affect the myelosuppresive action of microtubule-binding drugs. A polymorphism found in a tubulin isoform expressed only in hemapoietic cells may contribute to the patient variation in myelosuppression that occurs after treatment with microtubule-binding drugs. Cancer Res; 72(18); 4744-52. Ó2012 AACR.

show abstract

“…The mutant b1-tubulin protein Gln43Pro has been associated with abnormal platelet morphology, in vitro defects of platelet function, 9 and an increased risk of intracerebral hemorrhage. 15 We hypothesized that this mutation may cause the variation in platelet count, platelet size and bleeding tendency observed in subjects with the Bolzano mutation (see below). We, therefore, genotyped all patients carrying the Bolzano mutation and identified 22 homozygotes and 81 heterozygotes for the Gln43Pro mutation.…”

Section: B1-tubulin Polymorphismmentioning

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

View full text Add to dashboard Cite

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

show abstract

The association of the 1-tubulin Q43P polymorphism with intracerebral hemorrhage in men

Cited by 36 publications

References 27 publications

Mutation of the β1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly

Mutation of the β1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly

Hematologic β-Tubulin VI Isoform Exhibits Genetic Variability That Influences Paclitaxel Toxicity

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

Contact Info

Product

Resources

About