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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Available from: Manuela Germeshausen, Mar 04, 2015
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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.
    08/2013; 4(4):270-90. DOI:10.1177/2040620713498161
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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.
    Journal of Hematology & Oncology 01/2013; 6(1):11. DOI:10.1186/1756-8722-6-11 · 4.81 Impact Factor
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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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    ABSTRACT: The thrombopoietin receptor (TpoR) is a type I transmembrane protein that mediates the signaling functions of thrombopoietin (Tpo) in regulating megakaryocyte differentiation, platelet formation, and hematopoietic stem cell renewal. We probed the role of each of the four extracellular domain putative N-glycosylation sites for cell surface localization and function of the receptor. Single N-glycosylation mutants at any of the four sites were able to acquire the mature N-glycosylated pattern, but exhibited a decreased Tpo-dependent JAK2-STAT response in stably transduced Ba/F3 or Ba/F3-JAK2 cell lines. The ability of JAK2 to promote cell surface localization and stability of TpoR required the first N-glycosylation site (Asn117). In contrast, the third N-glycosylation site (Asn298) decreased receptor maturation and stability. TpoR mutants lacking three N-glycosylation sites were defective in maturation, but N-glycosylation on the single remaining site could be detected by sensitivity to PNGaseF. The TpoR mutant defective in all four N-glycosylation sites was severely impaired in plasma membrane localization and was degraded by the proteasome. N-glycosylation receptor mutants are not misfolded as, once localized on the cell surface in overexpression conditions, they can bind and respond to Tpo. Our data indicate that extracellular domain N-glycosylation sites regulate in a combinatorial manner cell surface localization of TpoR. We discuss how mutations around TpoR N-glycosylation sites might contribute to inefficient receptor traffic and disease.
    Frontiers in Endocrinology 11/2011; 2:71. DOI:10.3389/fendo.2011.00071
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