Advances in understanding the pathogenesis of primary familial and congenital polycythaemia

Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9039, USA.
British Journal of Haematology (Impact Factor: 4.71). 03/2010; 148(6):844-52. DOI: 10.1111/j.1365-2141.2009.08069.x
Source: PubMed


Primary familial and congenital polycythemia (PFCP) is an autosomal-dominant proliferative disorder characterized by erythrocytosis and hypersensitivity of erythroid progenitors to erythropoietin (Epo). Several lines of evidence suggest a causal role of truncated erythropoietin receptor (EpoR) in this disease. In this review, we discuss PFCP in the context of erythrocytosis and EpoR signalling. We focus on recent studies describing mechanisms underlying Epo-dependent EpoR down-regulation. One mechanism depends on internalization mediated through the p85 regulatory subunit of the Phosphoinositide 3-Kinase, and the other utilizes ubiquitin-based proteasomal degradation. Truncated PFCP EpoRs are not properly down-regulated upon stimulation, underscoring the importance of these mechanisms in the pathogenesis of PFCP.

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    • "La polyglobulie primitive familiale congénitale est une affection génétique rare de transmission autosomale dominante, décrite pour la première fois en 1991 dans plusieurs familles finlandaises [12,13]. Cette maladie est caractérisée par une hypersensibilité des progéniteurs érythroïdes à l'EPO, expliquée par des mutations génétiques de son récepteur14151617. Plus de 15 mutations différentes sont actuellement répertoriées, toutes concernant la partie du gène codant pour la région intracellulaire de l'EPO-r. "
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    ABSTRACT: La maladie de Vaquez et les polyglobulies secondaires acquises représentent la majorité des cas de polyglobulie rencontrée en pratique. Les polyglobulies héréditaires sont des maladies rares qui doivent être évoquées après élimination des causes acquises. Notre compréhension de ces pathologies s’est nettement améliorée durant ces dernières années, mais elles restent relativement méconnues du clinicien. Dans cette mise au point, nous passerons en revue les différentes causes de polyglobulies héréditaires et proposerons un algorithme diagnostique à suivre.
    Full-text · Article · Jan 2016
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    • "It is caused by a molecular defect in the hematopoietic progenitor cells. Previously diagnosed cases have been found to possess germline gain-of-function mutations in the Epo receptor gene (EPOR; MIM #133171) [Huang et al., 2010 and Table 1]. In contrast, secondary congenital erythrocytosis (CE) is often characterized by inappropriately normal or raised serum Epo [van Maerken et al., 2004]. "
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    ABSTRACT: Congenital Erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary congenital erythrocytosis arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1 and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive internet-based database focusing on the registration of clinical history, hematological, biochemical and molecular data ( In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database (LOVD). This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2013 · Human Mutation
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    • "Second, and likewise in an EPO dose-dependent fashion, the expression of truncated EPOR forms (EPOR-T-392 or EPOR-T-374) interestingly resulted in obvious decreases in levels of the co-expressed endogenous wild-type EPOR (Figures 8A and 8C). Third (and again somewhat unexpectedly) EPO dose-dependent turnover of truncated alleles to low Mr 24 K and Mr 22 K species (respectively) was obvious (Figure 8D) (despite prior hypotheses that internalization of such truncated EPOR alleles might be disabled) [15]. "
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    ABSTRACT: Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for erythropoiesis; can modulate non-erythroid target tissues; and have been reported to affect the progression of certain cancers. Basic studies of EPOR expression and trafficking, however, have been hindered by low-level EPOR occurrence, and the limited specificity of anti-EPOR antibodies. Consequently, these aspects of EPOR biology are not well defined, nor are actions of polycythemia- associated mutated EPOR alleles. Using novel rabbit monoclonal antibodies to intracellular, PY- activated and extracellular EPOR domains, the following properties of the endogenous hEPOR in erythroid progenitors first are unambiguously defined. 1) High- Mr EPOR forms become obviously expressed only when EPO is limited. 2) EPOR-68K plus -70K species sequentially accumulate, and EPOR-70K comprises an apparent cell surface EPOR population. 3) Brefeldin A, N-glycanase and associated analyses point to EPOR-68K as a core-glycosylated intracellular EPOR pool (of modest size). 4) In contrast to recent reports, EPOR inward trafficking is shown (in UT7epo cells, and primary proerythroblasts) to be sharply ligand-dependent. Beyond this, when C-terminal truncated hEPOR-T mutant alleles as harbored by polycythemia patients are co-expressed with the wild-type EPOR in EPO-dependent erythroid progenitors, several specific events become altered. First, EPOR-T alleles are persistently activated upon EPO- challenge, yet are also subject to apparent turn-over (to low-Mr EPOR products). Furthermore, during exponential cell growth EPOR-T species become both over-represented, and hyper-activated. Interestingly, EPOR-T expression also results in an EPO dose-dependent loss of endogenous wild-type EPOR's (and, therefore, a squelching of EPOR C-terminal- mediated negative feedback effects). New knowledge concerning regulated EPOR expression and trafficking therefore is provided, together with new insight into mechanisms via which mutated EPOR-T polycythemia alleles dysregulate the erythron. Notably, specific new tools also are characterized for studies of EPOR expression, activation, action and metabolism.
    Full-text · Article · Jan 2012 · PLoS ONE
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