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Genetic causes of erythrocytosis and the oxygen-sensing pathway.

ABSTRACT: Idiopathic erythrocytosis is an uncommon disease, and is defined by an increase in red blood cell mass. The differential diagnosis of erythrocytosis is extensive, and can be divided into primary and secondary forms. Primary erythrocytoses are due to intrinsic defects in erythroid precursor cells and are characterized by low erythropoietin levels. Secondary erythrocytoses are extrinsic to erythroid progenitors and are characterized by either high or inappropriately normal erythropoietin levels. A distinct subset of secondary erythrocytoses are due to genetic mutations in key proteins of the oxygen-sensing pathway. These proteins constitute the core molecular machinery of oxygen-sensing with respect to red blood cell control. Apart from assigning physiologic roles for these proteins, studies of these rare mutations have (i) revealed the exquisite sensitivity of this pathway to genetic perturbations, (ii) highlighted important functional regions of the proteins, and (iii) provided a basis for potentially targeting this pathway for therapeutic benefit.

SUBMITTER: Lee FS

PROVIDER: S-EPMC3400270 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Genetic causes of erythrocytosis and the oxygen-sensing pathway.

Lee Frank S FS

Blood reviews 20080605 6

Idiopathic erythrocytosis is an uncommon disease, and is defined by an increase in red blood cell mass. The differential diagnosis of erythrocytosis is extensive, and can be divided into primary and secondary forms. Primary erythrocytoses are due to intrinsic defects in erythroid precursor cells and are characterized by low erythropoietin levels. Secondary erythrocytoses are extrinsic to erythroid progenitors and are characterized by either high or inappropriately normal erythropoietin levels. A ...[more]

PMID: 18538455

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Investigation of genetic disturbances in oxygen sensing and erythropoietin signaling pathways in cases of idiopathic erythrocytosis.

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| S-EPMC3864166 | biostudies-literature

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The neuronal oxygen-sensing pathway controls postnatal vascularization of the murine brain.

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Oxygen sensing in embryo culture

Project description:This series compares the effects that two pharmacologically distinct ligands at the mitochondrial peripheral-type benzodiazepine receptor (Bzrp) has on gene expression in early mouse embryos cultured under different oxygen levels. Mouse embryos averaging 16-18 somite pairs were explanted on 9 d.p.c. and grown in culture under optimal oxygenation (21% oxygen, hyperbaric with respect to arterial blood = 80-100 mmHg). Most embryos (>90%) develop normally in over a 24h culture period. When embryos receive suboptimal oxygenation for 2.0h (5% oxygen, similar to venous blood = 38-40 mmHg) a high percentage of them (>60%) go on to develop abnormally or else fail. These hypoxic embryos are remediated with 5 uM PK11195 to ~25% malformation rate. Cultured embryos were exposed to different oxygen levels (5% or 21%) in the presence of the Bzrp ligands PK11195 (Bzrp antagonist) versus Ro5-4864 (Bzrp agonist). The sampling time was guided by p53 protein induction with hypoxia, and remediation with PK11195, at 4.0h of culture and exposures. Thus all measurements were on RNA from the prosencephalon collected 2.0h after start of the test period on 9 d.p.c. Keywords = peripheral benzodiazepine receptor Keywords = oxygen sensing Keywords = Bzrp ligands Keywords = PK11195 Keywords = Ro5-4864 Keywords = embryo Keywords = p53 protein induction Keywords: ordered

2004-03-11 | GSE1079 | GEO

The NOTCH1-dependent HIF1α/VGLL4/IRF2BP2 oxygen sensing pathway triggers erythropoiesis terminal differentiation.

Project description:Hypoxia is widely considered as a limiting factor in vertebrate embryonic development, which requires adequate oxygen delivery for efficient energy metabolism, while nowadays some researches have revealed that hypoxia can induce stem cells so as to improve embryonic development. Erythroid differentiation is the oxygen delivery method employed by vertebrates at the very early step of embryo development, however, the mechanism how erythroid progenitor cell was triggered into mature erythrocyte is still not clear. In this study, after detecting the upregulation of vgll4b in response to oxygen levels, we generated vgll4b mutant zebrafish using CRISPR/Cas9, and verified the resulting impaired heme and dysfunctional erythroid terminal differentiation phenotype. Neither the vgll4b-deficient nor the γ-secretase inhibitor IX (DAPT)-adapted zebrafish were able to mediate HIF1α-induced heme generation. In addition, we showed that vgll4b mutant zebrafish were associated with an impaired erythroid phenotype, induced by the downregulation of alas2, which could be rescued by irf2bp2 depletion. Further mechanistic studies revealed that zebrafish VGLL4 sequesters IRF2BP2, thereby inhibiting its repression of alas2 expression and heme biosynthesis. These processes occur primarily via the VGLL4 TDU1 and IRF2BP2 ring finger domains. Our study also indicates that VGLL4 is a key player in the mediation of NOTCH1-dependent HIF1α-regulated erythropoiesis and can be sensitively regulated by oxygen concentrations. On the other hand, VGLL4 is a pivotal regulator of heme biosynthesis and erythroid terminal differentiation, which collectively improve oxygen metabolism.

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Oxygen sensing in embryo culture

2010-06-09 | E-GEOD-1079 | biostudies-arrayexpress

Genetic variants of erythropoietin (EPO) and EPO receptor genes in familial erythrocytosis.

Project description:ObjectivesErythrocytosis is characterized by the expansion of erythrocyte compartment including elevated red blood cell number, hematocrit, and hemoglobin content. Familial erythrocytosis (FE) is a congenital disorder with different genetic background. Type 1 FE is primary FE caused by mutation in erythropoietin receptor gene (EPOR). Type 2-5 FE are secondary FEs caused by mutations of genes involved in oxygen sensing pathway important for erythropoietin (EPO) regulation. In the present study, we summarized associations between EPOR and EPO gene variations with development of FE and searched for genetic variants located within regulatory regions.MethodsPublications reporting EPOR and EPO sequence variants associated with FE or clinical features of erythrocytosis were retrieved from PubMed and WoS. In silico, sequence reanalysis was performed using Ensembl genomic browser, release 89 to screen for variants located within regulatory regions.ResultsTo date, 28 variants of the EPOR and seven variants of the EPO gene have been associated with erythrocytosis or upper hematocrit. Sequence variants were also found to be present within regulatory regions.ConclusionsRole of variants in regulatory regions of the EPO gene should be further investigated.

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