Congenital erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular-genetic analysis of 21 Czech patients with congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and iron homoeostasis. Causative mutations in erythropoietin receptor (EPOR), hypoxia-inducible factor 2 alpha (HIF2A) or Von Hippel-Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or Janus kinase 2 (JAK2) variants with other genetic/non-genetic factors in erythrocytosis manifestation may involve variants of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) or Ten-eleven translocation 2 (TET2), but this requires further research. In two families, hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or hepcidin levels was observed in our cohort. VHL- and HIF2A-mutant erythrocytosis showed increased erythroferrone and suppressed hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or therapy. Understanding the interplay between iron metabolism and erythropoiesis in different subgroups of congenital erythrocytosis may improve current treatment options.
- MeSH
- hepcidiny genetika MeSH
- iontové kanály genetika MeSH
- kyslík metabolismus MeSH
- lidé MeSH
- mutace MeSH
- polycytemie * genetika MeSH
- receptory erythropoetinu genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Iron availability for erythropoiesis is controlled by the iron-regulatory hormone hepcidin. Increased erythropoiesis negatively regulates hepcidin synthesis by erythroferrone (ERFE), a hormone produced by erythroid precursors in response to erythropoietin (EPO). The mechanisms coordinating erythropoietic activity with iron homeostasis in erythrocytosis with low EPO are not well defined as exemplified by dominantly inherited (heterozygous) gain-of-function mutation of human EPO receptor (mtHEPOR) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this mtHEPOR that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3-6 weeks of age. Prenatally and perinatally, mtHEPOR heterozygous and homozygous mice (differing in erythrocytosis severity) had increased Erfe transcripts, reduced hepcidin, and iron deficiency. Epo was transiently normal in the prenatal life; then decreased at postnatal day 7, and remained reduced in adulthood. Postnatally, hepcidin increased in mtHEPOR heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially mtHEPOR homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, mtHEPOR erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age-related attenuation, likely contributes to increased iron deposition in the aged mtHEPOR mice. In conclusion, the erythroid drive-mediated inhibition of hepcidin production in mtHEPOR mice in the prenatal/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between mtHEPOR heterozygotes and homozygotes suggest dose-dependent alterations of downstream EPOR stimulation.
- MeSH
- aktivační mutace MeSH
- dospělí MeSH
- erythropoetin * genetika farmakologie MeSH
- erytropoéza genetika MeSH
- hepcidiny genetika metabolismus MeSH
- hormony MeSH
- lidé MeSH
- myši MeSH
- polycytemie * genetika MeSH
- receptory erythropoetinu genetika metabolismus MeSH
- senioři MeSH
- železo metabolismus MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- myši MeSH
- senioři MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- biologické markery MeSH
- dospělí MeSH
- exprese genu * MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa genetika metabolismus MeSH
- hodnocení rizik MeSH
- hypoxie genetika metabolismus MeSH
- incidence MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorový supresorový protein VHL genetika MeSH
- následné studie MeSH
- polycytemie komplikace genetika metabolismus MeSH
- prognóza MeSH
- proporcionální rizikové modely MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- thrombospondin 1 genetika MeSH
- trombóza krev diagnóza epidemiologie etiologie MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
UNLABELLED: Mutations of the truncated cytoplasmic domain of human erythropoietin receptor (EPOR) result in gain-of-function of erythropoietin (EPO) signaling and a dominantly inherited polycythemia, primary familial and congenital polycythemia (PFCP). We interrogated the unexplained transient absence of perinatal polycythemia observed in PFCP patients using an animal model of PFCP to examine its erythropoiesis during embryonic, perinatal, and early postnatal periods. In this model, we replaced the murine EpoR gene (mEpoR) with the wild-type human EPOR (wtHEPOR) or mutant human EPOR gene (mtHEPOR) and previously reported that the gain-of-function mtHEPOR mice become polycythemic at 3~6 weeks of age, but not at birth, similar to the phenotype of PFCP patients. In contrast, wtHEPOR mice had sustained anemia. We report that the mtHEPOR fetuses are polycythemic, but their polycythemia is abrogated in the perinatal period and reappears again at 3 weeks after birth. mtHEPOR fetuses have a delayed switch from primitive to definitive erythropoiesis, augmented erythropoietin signaling, and prolonged Stat5 phosphorylation while the wtHEPOR fetuses are anemic. Our study demonstrates the in vivo effect of excessive EPO/EPOR signaling on developmental erythropoiesis switch and describes that fetal polycythemia in this PFCP model is followed by transient correction of polycythemia in perinatal life associated with low Epo levels and increased exposure of erythrocytes' phosphatidylserine. We suggest that neocytolysis contributes to the observed perinatal correction of polycythemia in mtHEPOR newborns as embryos leaving the hypoxic uterus are exposed to normoxia at birth. KEY MESSAGE: Human gain-of-function EPOR (mtHEPOR) causes fetal polycythemia in knock-in mice. Wild-type human EPOR causes fetal anemia in knock-in mouse model. mtHEPOR mice have delayed switch from primitive to definitive erythropoiesis. Polycythemia of mtHEPOR mice is transiently corrected in perinatal life. mtHEPOR newborns have low Epo and increased exposure of erythrocytes' phosphatidylserine.
- MeSH
- aktivační mutace * MeSH
- anemie krev genetika metabolismus MeSH
- erythropoetin metabolismus MeSH
- erytrocyty metabolismus MeSH
- erytroidní prekurzorové buňky metabolismus MeSH
- erytropoéza genetika MeSH
- fosforylace MeSH
- genotyp MeSH
- hematokrit MeSH
- hemoglobiny genetika MeSH
- lidé MeSH
- myši transgenní MeSH
- myši MeSH
- polycytemie krev genetika metabolismus MeSH
- receptory erythropoetinu genetika metabolismus MeSH
- regulace genové exprese * MeSH
- signální transdukce MeSH
- transkripční faktor STAT5 metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
The role of somatic JAK2 mutations in clonal myeloproliferative neoplasms (MPNs) is well established. Recently, germ line JAK2 mutations were associated with polyclonal hereditary thrombocytosis and triple-negative MPNs. We studied a patient who inherited 2 heterozygous JAK2 mutations, E846D from the mother and R1063H from the father, and exhibited erythrocytosis and megakaryocytic atypia but normal platelet number. Culture of erythroid progenitors from the patient and his parents revealed hypersensitivity to erythropoietin (EPO). Using cellular models, we show that both E846D and R1063H variants lead to constitutive signaling (albeit much weaker than JAK2 V617F), and both weakly hyperactivate JAK2/STAT5 signaling only in the specific context of the EPO receptor (EPOR). JAK2 E846D exhibited slightly stronger effects than JAK2 R1063H and caused prolonged EPO-induced phosphorylation of JAK2/STAT5 via EPOR. We propose that JAK2 E846D predominantly contributes to erythrocytosis, but is not sufficient for the full pathological phenotype to develop. JAK2 R1063H, with very weak effect on JAK2/STAT5 signaling, is necessary to augment JAK2 activity caused by E846D above a threshold level leading to erythrocytosis with megakaryocyte abnormalities. Both mutations were detected in the germ line of rare polycythemia vera, as well as certain leukemia patients, suggesting that they might predispose to hematological malignancy.
- MeSH
- dospělí MeSH
- fosforylace MeSH
- Janus kinasa 2 genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- megakaryocyty metabolismus patologie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- polycytemie vrozené genetika MeSH
- receptory erythropoetinu genetika metabolismus MeSH
- signální transdukce MeSH
- transkripční faktor STAT5 genetika metabolismus MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
UNLABELLED: Backround. There is increasing evidence of the role of hypoxia or pseudohypoxia in tumorigenesis, including pheochromocytoma (PHEO) and paraganglioma (PGL). (Pseudo)hypoxia leads to activation of hypoxia-inducible transcription factors (HIFs) and thus, promotes the transcription of hypoxia-responsive genes which are involved in tumorigenesis. Recently identified is a new syndrome consisting of multiple and recurrent PGLs or PHEOs, somatostatinoma, and congenital polycythemia, due to somatic hypoxia-inducible factor 2α gene (HIF2A) mutations. METHODS AND RESULTS: PubMed and Web of Science online databases were used to search reviews and original articles on the HIF, PHEO/PGL, and Pacak-Zhuang syndrome. CONCLUSIONS: The novel somatic and germline gain-of-function HIF2A mutations described latterly emphasize the role of the HIF-2α in the PHEO/PGL development and these findings designate HIF, especially HIF-2α, as a promising treatment target.
- MeSH
- karcinogeneze genetika MeSH
- lidé MeSH
- mutace MeSH
- paragangliom farmakoterapie genetika MeSH
- polycytemie vrozené farmakoterapie genetika MeSH
- somatostatinom farmakoterapie genetika MeSH
- syndrom MeSH
- transkripční faktory bHLH genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- dítě MeSH
- esenciální trombocytemie farmakoterapie genetika komplikace MeSH
- financování organizované MeSH
- hematologické komplikace těhotenství MeSH
- Janus kinasa 2 genetika MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- následné studie MeSH
- polycytemie farmakoterapie genetika komplikace MeSH
- předškolní dítě MeSH
- receptory thrombopoetinu genetika MeSH
- retrospektivní studie MeSH
- substituce aminokyselin MeSH
- těhotenství MeSH
- trombocytóza farmakoterapie genetika komplikace MeSH
- výsledek těhotenství MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- souhrny MeSH
- MeSH
- diferenciální diagnóza MeSH
- erytropoéza fyziologie genetika imunologie MeSH
- financování organizované MeSH
- genetické nemoci vrozené diagnóza etiologie MeSH
- genetické techniky využití MeSH
- hypoxie buňky genetika imunologie MeSH
- lidé MeSH
- molekulární biologie MeSH
- polycytemie diagnóza etiologie genetika MeSH
- polymerázová řetězová reakce metody využití MeSH
- receptory erythropoetinu krev MeSH
- transkripční faktory genetika krev MeSH
- Check Tag
- lidé MeSH
