HGNC Approved Gene Symbol: EPOR
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:11,377,207-11,384,314 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | [Erythrocytosis, familial, 1] | 133100 | Autosomal dominant | 3 |
Jones et al. (1990) isolated the human homolog of the murine erythropoietin (EPO; 133170) receptor (EPOR) from an erythroleukemia cell line and from fetal liver. Both the cDNA and the protein sequence of the human receptor were 82% homologous to the murine receptor. Heterologous expression of the human cDNA in COS cells yielded a 508-amino acid protein with a molecular mass of approximately 66 kD.
D'Andrea and Zon (1990) provided a review of the erythropoietin receptor.
Noguchi et al. (1991) isolated and characterized a genomic clone of human EPOR from a placenta genomic library using a cDNA probe for the murine gene. The coding region spans about 6.5 kb with 7 introns ranging in size from 81 bp to 2.1 kb. Maouche et al. (1991) obtained similar results. A high degree of sequence homology (81.6% in the coding region) and similarity in structural organization was found with the murine counterpart.
Penny and Forget (1991) reported that the coding region of the EPOR gene is contained within 8 exons spanning approximately 6 kb. It has much structural and sequence similarity to the murine gene, which was used in isolating the human genomic clone. Its organization was also shown to be homologous to that of the IL2RB gene (146710).
Budarf et al. (1990) mapped the EPOR gene to human 19pter-q12 by somatic cell hybrid analysis. In the mouse, they showed by interspecific backcross mapping that the locus is tightly linked to the murine Ldlr locus near the centromere of chromosome 9. This region of mouse chromosome 9 is homologous to human 19p13, strongly suggesting that the human EPOR gene is in 19p13. Winkelmann et al. (1990) found 2 distinct, short stretches of 3-prime untranslated sequence homology between human and murine cDNAs. They localized the human gene to 19p13.3-p13.2 by in situ hybridization and confirmed the assignment by hybridization to a panel of sorted human chromosomes. Using a highly informative (polymorphism information element, PIC, = 0.86) simple sequence repeat polymorphism at the 5-prime end of the EPOR gene, Sistonen et al. (1993) placed the EPOR gene on the genetic map of 19p through studies of 12 CEPH families.
Akashi et al. (2000) reported the prospective identification, purification, and characterization, using cell surface markers and flow cytometry, of a complementary clonogenic common myeloid progenitor that gives rise to all myeloid lineages. The distinction between the common lymphoid progenitor and common myeloid progenitor is that the common lymphoid progenitor expresses IL7 receptor (146661) and does not express MPL (159530), whereas the common myeloid progenitor does not express the IL7 receptor and expresses MPL. Further differentiation of the common myeloid progenitor into the granulocyte/monocyte progenitor versus the megakaryocyte/erythrocyte progenitor is dependent upon the expression of the EPOR. The myeloid/erythroid progenitor expresses the EPOR, whereas the granulocyte/monocyte progenitor does not. Akashi et al. (2000) proposed that the common lymphoid progenitor and common myeloid progenitor populations reflect the earliest branch points between the lymphoid and myeloid lineages, and that the commitment of common myeloid progenitors to either the megakaryocyte/erythrocyte or the granulocyte/macrophage lineages are mutually exclusive events.
Becker et al. (2010) showed by mathematical modeling of quantitative data and experimental validation that rapid ligand depletion and replenishment of the cell surface receptor are characteristic features of the EPO receptor. The amount of EPO-EPOR complexes and EPOR activation integrated over time corresponds linearly to ligand input; this process is carried out over a broad range of ligand concentrations. This relation depends solely on EPOR turnover independent of ligand binding, which suggests an essential role of large intracellular receptor pools. Becker et al. (2010) concluded that these receptor properties enable the system to cope with basal and acute demand in the hematopoietic system.
Khalil et al. (2018) identified surface modulation of EPOR as a critical component of the erythroid iron deprivation response. Iron deprivation significantly decreased surface EPOR levels and affected capacity for downstream signaling in human cells, and knockin mice with enforced surface retention of Epor failed to develop anemia with iron deprivation. Further investigation identified SCRIB (607733) as an iron response factor regulated by the erythroid iron-deprivation response that influenced surface EPOR display. Immunofluorescence analysis of iron-replete erythroblasts revealed that SCRIB was concentrated at the cell periphery, but it also distributed throughout the cytoplasm in a vesicular pattern. Erythroid iron deprivation caused downregulation of SCRIB through mediation of cathepsin (see 613111) and the iron-sensing transferrin receptor-2 (TFR2; 604720). SCRIB deficiency in turn reduced surface expression of EPOR but selectively retained survival signaling via AKT (164730), thereby providing a means for integration of iron sensing with receptor function to permit modulation of progenitor expansion without compromising survival.
Erythrocytosis 1
In all 29 affected members of a large Finnish family with autosomal dominant erythrocytosis-1 (ECYT1; 133100) due to increased sensitivity to erythropoietin (Juvonen et al., 1991), de la Chapelle et al. (1993) identified a heterozygous mutation in the EPOR gene (133171.0001).
In 2 unrelated families with autosomal dominant erythrocytosis, Kralovics et al. (1997) identified 2 different heterozygous mutations in the EPOR gene (133171.0004; 133171.0005). The authors noted that most of the described EPOR mutations (6 of 8) associated with ECYT1 resulted in an absence of the C-terminal negative regulatory domain of the receptor.
Associations Pending Confirmation
Ward et al. (1992) performed restriction endonuclease mapping of the EPOR gene in a human erythroleukemia (see 133180) cell line that overexpressed the EPOR gene and proliferated in response to erythropoietin. They demonstrated a 3-prime end deletion of one EPOR gene and raised the possibility of the role of the abnormality in the pathogenesis of the erythroleukemia from which the cell line was derived.
Exclusion Studies
Hess et al. (1994) found no evidence of mutations in the EPOR gene among 24 patients with polycythemia vera (PV; 263300).
In the mouse, Longmore and Lodish (1991) showed that a point mutation at codon 129 of the Epor gene resulted in constitutive activation. The mice developed erythrocytosis and splenomegaly. From the spleen of these animals, the authors isolated clonal, growth factor-independent, proerythroblast cell lines that expressed Epor and had rearranged and inactivated expression of the p53 suppressor oncogene. The observations demonstrated that oncogenic point mutations occur in a member of the cytokine receptor superfamily. The activated Epor did not transform cultured fibroblasts, however, suggesting why oncogenic mutations in other members of this receptor superfamily had not been detected.
Mutagenesis and transfection experiments have shown that truncation of the cytoplasmic domain of the erythropoietin receptor in mice can cause increased activity (D'Andrea et al., 1991).
Divoky et al. (2001) replaced the murine Epor gene with a wildtype human EPOR gene and a mutant human EPOR gene (Y426X; 133171.0006) that had initially been identified in a patient with familial erythrocytosis. Mice heterozygous for the mutant human allele mimicked the human disorder. Mice that were homozygous for the mutant human allele were severely polycythemic but viable. The results provided a model for functional studies of EPOR-triggered signaling pathways in erythropoiesis.
Mice lacking Epor exhibit severe anemia and die at about embryonic day 13.5. Yu et al. (2001) showed that this phenotype can be rescued by the human EPOR transgene. Furthermore, the cardiac defect associated with embryos lacking Epor was corrected and the increased apoptosis in fetal liver, heart, and brain in the Epor-null phenotype was markedly reduced.
In all 29 affected members of a large Scandinavian kindred with familial erythrocytosis-1 (ECYT1; 133100) reported by Juvonen et al. (1991), de la Chapelle et al. (1993) identified a heterozygous 6002G-A transition in exon 8 of the EPOR gene, resulting in a trp439-to-ter (W439X) substitution predicted to truncate the receptor by 70 amino acids at the C-terminal cytoplasmic domain. The phenotype was mild in all individuals; the proband won 3 Olympic gold medals in cross-country skiing. De la Chapelle (2005) pointed out that the family he studied were Finnish and Swedish Laplanders.
Percy et al. (1998) found the W439X mutation as a de novo event in an English boy with erythrocytosis.
In affected members of a family with autosomal dominant familial erythrocytosis-1 (ECYT1; 133100), Sokol et al. (1995) identified a heterozygous 1-bp insertion (5975insG) in the EPOR gene, resulting in truncation of the last 64 amino acids. Wildtype and mutant EPOR transcripts were detected in erythroid progenitors from affected individuals. The point in the family where the mutation originated could be identified.
This variant, formerly titled ERYTHROCYTOSIS, FAMILIAL, 1, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In a patient with erythrocytosis (ECYT1; 133100), Le Couedic et al. (1996) identified a heterozygous 6146A-G transition in exon 8 of the EPOR gene, resulting in an asn487-to-ser (N487S) substitution. The N487S substitution was not found in 21 other patients with polycythemia of unknown origin or in 51 normal controls. The EPOR mutation in both cases was found in EBV-derived cell lines, suggesting that it was germline and not somatic, although no familial cases were found. Although functional expression studies were inconclusive, Le Couedic et al. (1996) noted that the N487S substitution is located in the negative regulatory domain of the protein and speculated that this phosphopeptide sequence may play an important role in erythropoietin signaling.
Le Couedic et al. (1996) also found this variant in 1 of 10 cases of erythroleukemia (see 133180), but in that patient Mitjavila et al. (1991) had previously shown that erythroid growth was due to autocrine stimulation by erythropoietin. Although the role of the N487S substitution in erythroleukemia was unclear, Le Couedic et al. (1996) noted that mutations in the Epor gene had been described in experimental erythroleukemia in mice.
Hamosh (2018) found that this variant was present in heterozygous state in 690 of 120,744 alleles and in 5 homozygotes, with an allele frequency of 0.005715, in the ExAC database (November 5, 2018).
In affected members of a family with dominantly inherited familial erythrocytosis (ECYT1; 133100), Arcasoy et al. (1997) identified a heterozygous 7-bp deletion (nucleotides 5985 to 5991) in exon 8 of the EPOR gene, resulting in an EPOR peptide that was truncated by 59 amino acids at its C terminus. A 7-bp direct repeat was present in the normal EPOR gene at the site of this mutation, consistent with the slipped mispairing model for the generation of short deletions during DNA replication. Hypersensitivity to erythropoietin of erythroid progenitors from an affected individual was observed in in vitro methylcellulose cultures, as indicated by more numerous and larger colonies compared with those of the control subject. The proband had been evaluated at 15 years of age because of persistent headaches. There was no hypertension or cardiovascular disease in the family.
Kralovics et al. (1997) screened for mutations in the cytoplasmic domain of the EPO receptor (exons 7 and 8) in 27 unrelated subjects with primary or unidentified erythrocytosis. A Caucasian family from Ohio had the 7-bp deletion.
In affected members of a Caucasian family from the Czech Republic with autosomal dominant benign erythrocytosis (ECYT1; 133100), Kralovics et al. (1997) identified a 1-bp insertion (5967insT) in the EPOR gene.
In 3 affected members of a family with familial erythrocytosis (ECYT1; 133100) originally reported by Prchal et al. (1985), Kralovics et al. (1998) identified a heterozygous 5964C-G transversion in exon 8 of the EPOR gene, resulting in a tyr426-to-ter (Y426X) substitution. The resultant mutant protein is truncated by 83 amino acids and lacks 7 C terminal tyrosine residues. The mutant receptor exhibited hypersensitive erythropoietin-dependent proliferation compared to the wildtype EPOR when tested in a murine interleukin-3-dependent myeloid cell line. Kralovics et al. (1998) examined the segregation of the mutation in the family and found that a child in the third generation inherited the mutation but had no laboratory evidence of erythrocytosis. Furthermore, in vitro analysis of the erythroid progenitor cells of this affected child revealed hypersensitivity to erythropoietin, suggesting a defect at the level of progenitor cells. Failure of this child to develop the disorder suggested the existence of as yet unidentified environmental or genetic factors that suppress disease development.
Watowich et al. (1999) described a Swedish family with autosomal dominant familial erythrocytosis (ECYT1; 133100) which segregated with a direct tandem duplication of nucleotides 5968 to 5975 of the EPOR gene. The duplication resulted in a frameshift beyond residue 405, introducing 25 amino acids not related to the EPOR, and a premature stop codon, deleting 79 residues at the C terminus of the receptor. Affected family members were plethoric and often had additional symptoms, including hypertension, headaches, dizziness, nosebleeds, and exertional dyspnea, which were most pronounced in the males. These symptoms were alleviated by phlebotomies, and phlebotomy treatment had been recommended. Watowich et al. (1999) found that cells engineered to concomitantly express the wildtype EPOR and duplication or 6002G-A (133171.0001) mutant EPORs were hypersensitive to EPO-stimulated proliferation and activation of JAK2 (147796) and STAT5 (601511). These results demonstrated that familial erythrocytosis is caused by hyperresponsiveness of receptor-mediated signaling pathways and that this is dominant with respect to wildtype EPOR signaling.
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de la Chapelle. Personal Communication. Columbus, Ohio 12/4/2005.
Divoky, V., Liu, Z., Ryan, T. M., Prchal, J. F., Townes, T. M., Prchal, J. T. Mouse model of congenital polycythemia: homologous replacement of murine gene by mutant human erythropoietin receptor gene. Proc. Nat. Acad. Sci. 98: 986-991, 2001. [PubMed: 11158582] [Full Text: https://doi.org/10.1073/pnas.98.3.986]
Hamosh, A. Personal Communication. Baltimore, Md. 11/5/2018.
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