MPL mutations in 23 patients suffering from congenital amegakaryocytic thrombocytopenia: the type of mutation predicts the course of the disease.

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
Human Mutation (Impact Factor: 5.05). 03/2006; 27(3):296. DOI: 10.1002/humu.9415
Source: PubMed

ABSTRACT Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome. Mutations in the gene for the thrombopoietin receptor MPL were defined as the molecular cause in CAMT patients. Extending our sequence analyses from eight to a total of now 23 CAMT patients we could verify our hypothesis of genotype-phenotype correlation in CAMT. Seven different mutations predicted to lead to a complete loss of function of the thrombopoietin receptor were found in 13 patients belonging to group CAMT I with persistently low platelet counts and a fast progression into pancytopenia. Nine different missense mutations were detected in 10 patients of group CAMT II, characterized by a transient increase in platelet counts over 50 nl(-1) during the first years of life. Using in vitro assays with hematopoietic progenitors from patients of both patient groups we could provide experimental evidence for a residual activity of the thrombopoietin receptor in CAMT II patients.

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    ABSTRACT: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare aetiology of central thrombocytopenia characterised by severe reduction or absence of megakaryocytes in the bone marrow. This disease is caused by mutations in the c-MPL gene encoding for the receptor of thrombopoietin (TPO). The clinical presentation is variable and can often be mistaken for foetal/neonatal alloimmune thrombocytopenia or idiopathic thrombocytopenic purpura. Because of treatment failure, a central thrombocytopenia is suspected. The diagnosis is made by the bone marrow examination, the dosage of TPO and identification of mutations in the c-MPL gene. The outcome is quickly pancytopenia. Description of four new single-center observations of patients treated for CAMT, who underwent allogeneic hematopoietic stem cell transplantation, allowed to focus on this disease and its therapeutic approach. According to the type of c-MPL mutations, a variable outcome has been discussed. Because of haemorrhagic risk and the possibility of a malignant evolution, a stem cell transplantation, being the only curative treatment, must be considered as soon as the diagnosis is established. Gene therapy might be an interesting future prospect.
    Revue d'Oncologie Hématologie Pédiatrique. 03/2014; 2(1):39–45.
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    ABSTRACT: Background The diagnostic evaluation of inherited platelet disorders (IPDs) is complicated and time-consuming, resulting in a relevant number of undiagnosed and incorrectly classified patients. In order to evaluate the spectrum of IPDs in individuals with clinical suspicion of these disorders, and to provide a diagnostic tool to centers not having access to specific platelets studies, we established the project ¿Functional and Molecular Characterization of Patients with Inherited Platelet Disorders¿ under the scientific sponsorship of the Spanish Society of Thrombosis and Haemostasis.Patients/methodsSubjects were patients from a prospective cohort of individuals referred for clinical suspicion of IPDs as well as healthy controls. Functional studies included light transmission aggregation, flow cytometry, and when indicated, Western-blot analysis of platelet glycoproteins, and clot retraction analysis. Genetic analysis was mainly performed by sequencing of coding regions and proximal regulatory regions of the genes of interest.ResultsOf the 70 cases referred for study, we functionally and molecularly characterized 12 patients with Glanzmann Thrombasthenia, 8 patients with Bernard Soulier syndrome, and 8 with other forms of IPDs. Twelve novel mutations were identified among these patients. The systematic study of patients revealed that almost one-third of patients had been previously misdiagnosed.Conclusions Our study provides a global picture of the current limitations and access to the diagnosis of IPDs, identifies and confirms new genetic variants that cause these disorders, and emphasizes the need of creating reference centers that can help health care providers in the recognition of these defects.
    Orphanet Journal of Rare Diseases 12/2014; 9(1):1. · 3.96 Impact Factor
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    ABSTRACT: Platelets are derived from megakaryocytes in the bone marrow that create the cellular machinery the platelet needs to participate in the different processes of primary hemostasis including adhesion, activation and clot formation at the site of injury. Defects related to megakaryocyte differentiation, platelet formation, and/or platelet function can result in bleeding. Patients with thrombopathies can present with mucous membrane bleeding but may also present with bleeding following trauma or surgery. In this review, we have classified inherited platelet bleeding disorders (IPD) according to their underlying defective pathway: transcription regulation, TPO signaling, cytoskeletal organization, apoptosis, granule trafficking, and receptor signaling. Platelet function testing has provided insights into the underlying molecular defects that can result in bleeding. A major step forward was made during the last 3 years using new-generation genetic approaches that resulted in the discovery of novel genes such as NBEAL2, RBM8A, ACTN1, and GFI1B for the well-known IPD that cause gray platelet syndrome, thrombocytopenia-absent radius syndrome, and autosomal dominant thrombocytopenias, respectively. In the near future, it is expected that a similar approach will identify many novel genes that cause IPD of unknown etiology, which are common. The future challenge will be to use a functional, systems biology approach to study the genes mutated in IPD and determine their roles in megakaryocyte and platelet biology and pathology.
    International journal of laboratory hematology 06/2014; 36(3). · 1.30 Impact Factor

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