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: 5.14). 03/2006; 27(3):296. DOI: 10.1002/humu.9415
Source: PubMed


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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    • "Two classes of mutations exist, with group CAMT I nonsense mutations leading to persistently low platelet counts and rapid progression to aplastic anemia. Group CAMT II missense mutations are associated with less severe thrombocytopenia and a longer latency to aplasia [Germeshausen et al. 2006]. In a review of 96 patients with CAMT, the rate of malignant transformation was 2% [Ballmaier and Germeshausen, 2011]. "
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    ABSTRACT: While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia.
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    • "This is because these mutations cause amino acid changes or mRNA splicing defects in CD110, which do not completely abrogate the function of CD110 but leave residual activity [28-30]. Two lines of evidence support this hypothesis: 1. TPO-driven signalling is significantly reduced but not eliminated in K562 cells with missense mutations in in vitro assays [29] and 2. Colony-forming cells derived from CAMT II patients with missense mutations remain reactive to TPO [28]. "
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    ABSTRACT: The human c-mpl gene (MPL) plays an important role in the development of megakaryocytes and platelets as well as the self-renewal of haematopoietic stem cells. However, numerous MPL mutations have been identified in haematopoietic diseases. These mutations alter the normal regulatory mechanisms and lead to autonomous activation or signalling deficiencies. In this review, we summarise 59 different MPL mutations and classify these mutations into four different groups according to the associated diseases and mutation rates. Using this classification, we clearly distinguish four diverse types of MPL mutations and obtain a deep understand of their clinical significance. This will prove to be useful for both disease diagnosis and the design of individual therapy regimens based on the type of MPL mutations.
    Full-text · Article · Jan 2013 · Journal of Hematology & Oncology
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    • "The important aminoacids for Tpo binding are underlined (Deane et al., 1997). In square () are depicted the aminoacids that are mutated in congenital amegakaryocytic thrombocytopenia (Ballmaier et al., 2001; Germeshausen et al., 2006; Tijssen et al., 2008; Fox et al., 2009) and in round circles () the aminoacids that are mutated in familial thrombocytosis (Moliterno et al., 2004; El-Harith El et al., 2009). TM, transmembrane region; aa, aminoacid; D1D2, sub-domains of the distal cytokine receptor module; D3D4, sub-domains of the proximal cytokine receptor module; NH2, N-terminus of the protein; COOH, C-terminus of the protein; X, any aminoacid. "
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