Deleterious mutation in the FYB gene is associated with congenital autosomal recessive small‐platelet thrombocytopenia

Levin, Carina; Koren, Ariel; Pretorius, Etheresia; Rosenberg, Nurit; Шенкман, Борис; Hauschner, Hagit; Zalman, Lucia; Khayat, Morad; Salama, Ihsan; Elpeleg, Orly; Shalev, Stavit A.

doi:10.1111/jth.12966

Cited by 56 publications

(39 citation statements)

References 27 publications

(51 reference statements)

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“…Thrombus formation after carotoid artery occlusion was also impaired (14). Only recently, a nonsense mutation in the human gene encoding for ADAP was reported to cause small-platelet thrombocytopenia and bleeding tendency in patients (15,16).…”

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confidence: 99%

Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP

et al. 2019

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The adhesion and degranulation-promoting adapter protein (ADAP) is expressed in T cells, NK cells, myeloid cells, and platelets. The involvement of ADAP in the regulation of receptor-mediated inside-out signaling leading to integrin activation is well characterized, especially in T cells and in platelets. Due to the fact that animal studies using conventional knockout mice are limited by the overlapping effects of the different ADAP-expressing cells, we generated conditional ADAP knockout mice (ADAP fl/fl PF4-Cre tg ) (PF4, platelet factor 4). We observed that loss of ADAP restricted to the megakaryocytic lineage has no impact on other hematopoietic cells even under stimulation conditions. ADAP fl/fl PF4-Cre tg mice showed thrombocytopenia in combination with reduced plasma levels of PF4 and transforming growth factor ␤1 (TGF-␤1). In vitro, platelets from these mice revealed reduced P-selectin expression, lower levels of TGF-␤1 release, diminished integrin ␣IIb␤3 activation, and decreased fibrinogen binding after stimulation with podoplanin, the ligand of C-type lectin-like receptor 2 (CLEC-2). Furthermore, loss of ADAP was associated with impaired CLEC-2-mediated activation of phospholipase C␥2 (PLC␥2) and extracellular signal-regulated kinase 1/2 (ERK1/2). Induction of experimental autoimmune encephalomyelitis (EAE) in mice lacking ADAP expression in platelets caused a more severe disease. In vivo administration of TGF-␤1 early after T cell transfer reduced EAE severity in mice with loss of ADAP restricted to platelets. Our results reveal a regulatory function of ADAP in platelets in vitro and during autoimmune disease EAE in vivo.

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confidence: 99%

Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP

et al. 2019

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“…It is a GOF variant that increased actin polymerization and abnormal actin structures with decreased proplatelet formation was found in patient‐derived megakaryocytes. A third form of inherited “micro”thrombocytopenia (in addition to WAS and ARPC1B) and bleeding was found to be due to recessive variants in FYB (or ADAP) . Bone marrow aspirate from 1 patient showed reduced numbers of mature multilobulated megakaryocytes and increased megakaryocytes with nuclear hypersegmentation, suggesting abnormal maturation of megakaryocytes.…”

Section: Expanding Spectrum Of Inherited Bleeding Disordersmentioning

confidence: 99%

High‐throughput sequencing for diagnosing platelet disorders: lessons learned from exploring the causes of bleeding disorders

Heremans

Freson

2018

Int J Lab Hematology

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Inherited platelet disorders (IPDs) are a heterogeneous group of disorders caused by multiple genetic defects. Obtaining a molecular diagnosis for IPD patients using a phenotype- and laboratory-based approach is complex, expensive, time-consuming, and not always successful. High-throughput sequencing (HTS) methods offer a genotype-based approach to facilitate molecular diagnostics. Such approaches are expected to decrease time to diagnosis, increase the diagnostic rate, and they have provided novel insights into the genotype-phenotype correlation of IPDs. Some of these approaches have also focused on the discovery of novel genes and unexpected molecular pathways which modulate megakaryocyte and platelet biology were discovered. A growing number of genetic defects underlying IPDs have been identified and we will here provide an overview of the diverse molecular players. Screening of these genes will deliver a genetic diagnosis for about 40%-50% of the IPDs patients and we will compare different HTS applications that have been developed. A brief focus on gene variant interpretation and classification in a diagnostic setting will be given. Although it is true that successes in diagnostics and gene discovery have been reached, a large fraction of patients still remains without a conclusive diagnosis. In these patients, the sum of non-diagnostic variants in known genes or in potential novel genes might only be proven informative in future studies with larger patient cohorts and by data sharing among the diverse genome medicine initiatives. Finally, we still do not understand the role of the non-coding genome space for IPDs.

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“…Although the effect of the mutation has yet to be determined, a role in megakaryopoiesis has been suggested due to a reduced percentage of mature megakaryocytes in the bone marrow [26]. …”

Section: Genes That Effect Megakaryocyte Differentiation and Maturationmentioning

confidence: 99%

Inherited thrombocytopenia: novel insights into megakaryocyte maturation, proplatelet formation and platelet lifespan

2016

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The study of patients with inherited bleeding problems is a powerful approach in determining the function and regulation of important proteins in human platelets and their precursor, the megakaryocyte. The normal range of platelet counts in the bloodstream ranges from 150 000 to 400 000 platelets per microliter and is normally maintained within a narrow range for each individual. This requires a constant balance between thrombopoiesis, which is primarily controlled by the cytokine thrombopoietin (TPO), and platelet senescence and consumption. Thrombocytopenia can be defined as a platelet count of less than 150 000 per microliter and can be acquired or inherited. Heritable forms of thrombocytopenia are caused by mutations in genes involved in megakaryocyte differentiation, platelet production and platelet removal. In this review, we will discuss the main causative genes known for inherited thrombocytopenia and highlight their diverse functions and whether these give clues on the processes of platelet production, platelet function and platelet lifespan. Additionally, we will highlight the recent advances in novel genes identified for inherited thrombocytopenia and their suggested function.

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Deleterious mutation in the FYB gene is associated with congenital autosomal recessive small‐platelet thrombocytopenia

Cited by 56 publications

References 27 publications

Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP

Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP

High‐throughput sequencing for diagnosing platelet disorders: lessons learned from exploring the causes of bleeding disorders

Inherited thrombocytopenia: novel insights into megakaryocyte maturation, proplatelet formation and platelet lifespan

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