DeCure for Primary familial polycythemia due to EPO receptor mutation
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for primary familial polycythemia due to EPO receptor mutation — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePrimary familial polycythemia due to EPO receptor mutation maps to a 5-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for primary familial polycythemia due to epo receptor mutation is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
erythropoietin receptor (EPOR) — EPOR is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet nh4drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8VUI · 2.1 Å · ligand AMMONIUM ION (NH4). Experimental structure, not a prediction.
What the evidence adds up to
In 27 unrelated subjects with primary or unidentified polycythemia, two new truncating mutations in the EPOR gene were found: a 7-bp deletion (del5985-5991) in a Caucasian family from Ohio and a 5967insT mutation in a Caucasian family from the Czech Republic. By 1997, six out of eight described EPOR mutations associated with primary familial and congenital polycythemia (PFCP) resulted in absence of the C-terminal negative regulatory domain of the receptor. In one of these families, erythroid progenitors in serum-containing cultures without added EPO mimicked the behaviour of polycythemia vera progenitors, but antibodies against EPO or the EPOR could distinguish the two disorders.
A family with autosomal dominant PFCP across three generations carried a C5964G mutation in exon VIII that changed tyrosine codon 426 to a stop codon, truncating the EPOR protein by 83 amino acids. The mutant receptor showed hypersensitive EPO-dependent proliferation in a murine myeloid cell line. However, a child in the third generation who inherited the mutation had no laboratory evidence of polycythemia, despite erythroid progenitor cells that were hypersensitive to EPO in vitro. The authors concluded that unidentified environmental or genetic factors may suppress disease development in some mutation carriers.
A later family carried a novel EPOR G1251T mutation (glutamate to stop at amino acid 393). Affected individuals showed a 20-fold increase in circulating endothelial precursors. CD34+ cells from these patients proliferated and differentiated towards the erythroid phenotype with minimal EPO, unlike polycythemia vera cells. The truncated EPOR accumulated on erythroid precursor membranes, probably due to loss of residues involved in EPO-dependent receptor internalisation and degradation. Mutated receptor expression in EPOR-negative cells led to EPOR and Stat5 phosphorylation, and patient erythroid precursors showed increased activation of EPOR, Stat5, and Erk1/2 pathways.
By 2022, 33 EPOR genetic variants had been reported in association with PFCP. Two patients with polycythemia in whom JAK2 pathogenic variants had been excluded were found to carry two novel EPOR variants. Both showed hypersensitivity to EPO in in vitro cultures. No treatment or management data are provided in these abstracts. What remains missing is systematic long-term follow-up of mutation carriers, particularly those without overt polycythemia; prospective studies of thrombotic or vascular risk in this population; and any clinical trial testing whether reduction of red cell mass improves outcomes in PFCP, as no such trial is reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood · 1997 · 127 citations · open access
Two New EPO Receptor Mutations: Truncated EPO Receptors Are Most Frequently Associated With Primary Familial and Congenital Polycythemias
AbstractPrimary polycythemias are caused by an acquired or inborn mutation affecting hematopoietic/erythroid progenitors that results in an abnormal response to hematopoietic cytokines. Primary familial and congenital polycythemia (PFCP; also known as familial erythrocytosis) is characterized by elevated red blood cell mass, low serum erythropoietin (EPO) level, normal oxygen affinity of hemoglobin, and typically autosomal dominant inheritance. In this study we screened for mutations in the cytoplasmic domain of the EPO receptor (EPOR; exons 7 and 8 of the EPOR gene) in 27 unrelated subjects with primary or unidentified polycythemia. Two new EPOR mutations were found, which lead to truncation of the EPOR similarly to previously described mutations in PFCP subjects. The first is a 7-bp deletion (del5985-5991) found in a Caucasian family from Ohio. The second mutation (5967insT) was found in a Caucasian family from the Czech Republic. In both cases the EPO dose responses of the erythroid progenitors of the affected subjects were examined to confirm the diagnosis of PFCP. In one of these families, the in vitro behavior of erythroid progenitors in serum-containing cultures without the addition of EPO mimicked the behavior of polycythemia vera progenitors; however, we show that antibodies against either EPO or the EPOR distinguish the in vitro growth abnormality of polycythemia vera erythroid progenitors from that seen in this particular PFCP family. We conclude that PFCP is a disorder that appears to be associated in some families with EPOR mutations. So far, most of the described EPOR mutations (6 out of 8) associated with PFCP result in an absence of the C-terminal negative regulatory domain of the receptor.
Journal of Clinical Investigation · 1998 · 56 citations · open access
Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia.
AbstractPrimary familial and congenital polycythemia (PFCP or familial erythrocytosis) is a rare proliferative disorder of erythroid progenitor cells, characterized by elevated erythrocyte mass and hemoglobin concentration, hypersensitivity of erythroid progenitors to erythropoietin (EPO), and autosomal dominant inheritance or sporadic occurrence. A number of EPO receptor (EPOR) mutations were found in subjects with PFCP; most of these mutations resulted in the truncation of the COOH-terminal of the EPOR protein. We studied a family with autosomal dominant inheritance of PFCP in which four subjects were affected in three generations. We screened the affected individuals for EPOR gene mutations using SSCP analysis and found a C5964G mutation in exon VIII that changes tyrosine codon 426 to a translation termination codon resulting in an EPOR protein truncated by 83 amino acids. The mutant C5964G-EPOR exhibited hypersensitive EPO-dependent proliferation compared to the wild-type EPOR when tested in a murine interleukin-3-dependent myeloid cell line (FDC-P1). We also examined the segregation of the mutation with PFCP in the family and found that a child in the third generation inherited the mutation without having laboratory evidence of polycythemia. Further in vitro analysis of the erythroid progenitor cells of this affected child revealed that the progenitor cells were hypersensitive to EPO (a hallmark of PFCP) suggesting the presence of the disease at the level of progenitor cells. Failure of this child to develop polycythemia suggests the existence of as yet unidentified environmental or genetic factors that may suppress disease development.
AbstractBACKGROUND: Gain-of-function of erythropoietin receptor (EPOR) mutations represent the major cause of primary hereditary polycythemia. EPOR is also found in non-erythroid tissues, although its physiological role is still undefined. METHODOLOGY/PRINCIPAL FINDINGS: We describe a family with polycythemia due to a heterozygous mutation of the EPOR gene that causes a G-->T change at nucleotide 1251 of exon 8. The novel EPOR G1251T mutation results in the replacement of a glutamate residue by a stop codon at amino acid 393. Differently from polycythemia vera, EPOR G1251T CD34(+) cells proliferate and differentiate towards the erythroid phenotype in the presence of minimal amounts of EPO. Moreover, the affected individuals show a 20-fold increase of circulating endothelial precursors. The analysis of erythroid precursor membranes demonstrates a heretofore undescribed accumulation of the truncated EPOR, probably due to the absence of residues involved in the EPO-dependent receptor internalization and degradation. Mutated receptor expression in EPOR-negative cells results in EPOR and Stat5 phosphorylation. Moreover, patient erythroid precursors present an increased activation of EPOR and its effectors, including Stat5 and Erk1/2 pathway. CONCLUSIONS/SIGNIFICANCE: Our data provide an unanticipated mechanism for autosomal dominant inherited polycythemia due to a heterozygous EPOR mutation and suggest a regulatory role of EPO/EPOR pathway in human circulating endothelial precursors homeostasis.
Identification of Two Novel EPOR Gene Variants in Primary Familial Polycythemia: Case Report and Literature Review
AbstractPrimary familial and congenital polycythemia is a rare disease characterized by an increase in red cell mass that may be due to pathogenic variants in the EPO receptor (EPOR) gene. To date, 33 genetic variants have been reported to be associated. We analyzed the presence of EPOR variants in two patients with polycythemia in whom JAK2 pathogenic variants had been previously discarded. Molecular analysis of the EPOR gene was performed by Sanger sequencing of the coding regions and exon/intron boundaries of exon 8. We performed in vitro culture of erythroid progenitor cells. Segregation studies were done whenever possible. The two patients studied showed hypersensitivity to EPO in in vitro cultures. Analysis of the EPOR gene unveiled two novel pathogenic variants. Genetic testing of asymptomatic relatives could guarantee surveillance and proper management.
Guoji shuxue ji xueyexue zazhi · 2018 · 0 citations
Advances of molecular pathogenesis in polycythemia vera
AbstractPolycythemia vera (PV) is a clonal hematopoietic stem cell disorder with unknown etiology. Patients with PV often have headaches, itching, splenomegaly, thrombosis and gastrointestinal bleeding.PV has capability progress to myelofibrosis and acute leukemia. Pathogenic mechanism of PV may be related to many factors, such as growth factors and their receptors, signal pathway and key enzyme abnormalities, chromosome abnormality and gene mutations.The reveal of the molecular mechanism of PV helps to find new diagnostic and medicinal targets in clinic, so as to provide references for diagnosis, treatment and prognosis of PV patients. This article summarizes the progress of these related factors in PV.
Key words:
Polycythemia vera; Receptors, growth factor; Signal transduction; Chromosome aberrations; Mutation
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
