A A386G biallelic GPIb  gene mutation with anomalous behavior: a new mechanism suggested for Bernard-Soulier syndrome pathogenesis

Vettore, Silvia; Tezza, Fabiana; Malara, Alessandro; Vianello, Fabrizio; Pecci, Alessandro; Scandellari, Raffaella; Floris, Matteo; Balduini, Alessandra; Fabris, Fabrizio

doi:10.3324/haematol.2010.039008

Cited by 14 publications

(12 citation statements)

References 26 publications

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“…Mks of patients with biallelic BSS show normal in vitro differentiation and maturation (Balduini et al , ; Vettore et al , ), in agreement with the earlier observation of a normal or increased number of Mks in patients' BM (Tomer et al , ). However, Mks cultured from these subjects do not extend proplatelets, suggesting that thrombocytopenia derives from a defect of the latest phases of megakaryopoiesis.…”

Section: Lessons In Proplatelet Formation and Platelet Releasesupporting

confidence: 82%

“…An important issue is which of the properties of the GPIb‐IX‐V complex is essential for platelet biogenesis. In Mks of BSS patients, the defects in PPF were evident not only upon adhesion to VWF, but also when Mks were cultured in suspension or upon adhesion to fibrinogen (Balduini et al , ; Vettore et al , ). Similar observations were made with Mks of GPIbβ‐null mice, which showed the same PPF abnormalities when observed within animal BM or when cultured in suspension (Strassel et al , ).…”

Section: Lessons In Proplatelet Formation and Platelet Releasementioning

confidence: 99%

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Lessons in platelet production from inherited thrombocytopenias

Pecci

Balduini

2014

Br J Haematol

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SummaryOur knowledge of the cellular and molecular mechanisms of platelet production has greatly expanded in recent years due to the opportunity to culture in vitro megakaryocytes and to create transgenic animals with specific genetic defects that interfere with platelet biogenesis. However, in vitro models do not reproduce the complexity of the bone marrow microenvironment where megakaryopoiesis takes place, and experience shows that what is seen in animals does not always happen in humans. So, these experimental models tell us what might happen in humans, but does not assure us that these events really occur. In contrast, inherited thrombocytopenias offer the unique opportunity to verify in humans the actual effects of abnormalities in specific molecules on platelet production. There are currently 20 genes whose defects are known to result in thrombocytopenia and, on this basis, this review tries to outline a model of megakaryopoiesis based on firm evidence. Inherited thrombocytopenias have not yet yielded all the information they can provide, because nearly half of patients have forms that do not fit with any known disorder. So, further investigation of inherited thrombocytopenias will advance not only the knowledge of human illnesses, but also our understanding of human platelet production.

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Section: Lessons In Proplatelet Formation and Platelet Releasesupporting

confidence: 82%

Section: Lessons In Proplatelet Formation and Platelet Releasementioning

confidence: 99%

Lessons in platelet production from inherited thrombocytopenias

Pecci

Balduini

2014

Br J Haematol

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“…In the first variant, a mutation in the 5′UTR region of GP1BB impairs GATA1 binding (Ludlow et al , ) and leads to a decrease in the GP1BB transcript level. In the second variant, a biallelic N110E mutation in GP1BA modifies the proper maturation of the transcript (Vettore et al , ).…”

Section: Classical Inherited Macrothrombocytopenias That Are Identifimentioning

confidence: 99%

Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias

Favier

Raslová

2015

Br J Haematol

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SummaryThe inherited macrothrombocytopenias constitute a subgroup of congenital platelet disorders that is the best characterized from the genetic point of view. This clinically heterogeneous subgroup is characterized by a variable degree of bleeding but without predisposition to haematological malignancies, as seen in the two other subgroups. The classification of inherited thrombocytopenia is traditionally based on the description of different clinical and biological features, in particular the measurement of the mean platelet volume. In certain disorders, biochemical platelet components are abnormal, and their analyses are useful in diagnosis. However, these approaches present several limitations, and many cases remain undiagnosed, especially for patients without a clear family history. An analysis of genetic abnormalities was subsequently used for classification, demonstrating that some different clinical entities were, in fact, identical. The genomic approach that was used initially to accurately link some phenotypic diagnoses with the causal genetic alteration was positional cloning and DNA sequencing. More recently, next generation sequencing in the form of whole-genome or -exome sequencing and RNA sequencing has been developed. This review will focus on the progress in understanding the different macrothrombocytopenias that have been identified.

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“…Amino acids within GPIbα that have been documented to directly interact with the A1 domain of VWF have been identified in the N‐terminal flank (S11, H12, E14, N16), in the LRR region (H37, E128, K152, D175, T176, F199), and in the C‐terminal flank (E225, N226, Y228, S241) . Mutations in the N‐terminal flank and in the LRR have been associated with Bernard Soulier syndrome, a disorder in which GPIbα is either reduced or dysfunctional (Figure ) . The overall curvature of the VWF‐binding domain allows the N‐terminal flank and the C‐terminal flank to interact with each other intramolecularly .…”

Section: Introductionmentioning

confidence: 99%