A novel mutation of the erythropoietin receptor gene associated with primary familial and congenital polycythaemia

O'Rourke, Kacey M; Fairbairn, David J.; Jackson, Kathryn A.; Morris, Kirk; Tey, Siok-Keen; Kennedy, Glen

doi:10.1007/s12185-011-0813-z

Cited by 8 publications

(2 citation statements)

References 17 publications

(27 reference statements)

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“…Most of the PFCP-inducing mutations in EPOR result in a C-terminal truncated receptor that lacks the negative regulatory domain (Kralovics & Prchal, 2001;O'Rourke et al, 2011). However, so far, no missense mutations have been identified as the cause of PFCP, despite of the fact that they are found in PFCP patients (Kralovics & Prchal, 2001;Gordeuk et al, 2005;Percy & Lee, 2008).…”

Section: Discussionmentioning

confidence: 99%

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Polycythaemia-inducing mutations in the erythropoietin receptor (EPOR): mechanism and function as elucidated by epidermal growth factor receptor-EPOR chimeras

et al. 2014

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SummaryPrimary familial and congenital polycythaemia (PFCP) is a disease characterized by increased red blood cell mass, and can be associated with mutations in the intracellular region of the erythropoietin (EPO) receptor (EPOR). Here we explore the mechanisms by which EPOR mutations induce PFCP, using an experimental system based on chimeric receptors between epidermal growth factor receptor (EGFR) and EPOR. The design of the chimeras enabled EPOR signalling to be triggered by EGF binding. Using this system we analysed three novel EPOR mutations discovered in PFCP patients: a deletion mutation (Del1377-1411), a nonsense mutation (C1370A) and a missense mutation (G1445A). Three different chimeras, bearing these mutations in the cytosolic, EPOR region were generated; Hence, the differences in the chimera-related effects are specifically attributed to the mutations. The results show that the different mutations affect various aspects related to the signalling and metabolism of the chimeric receptors. These include slower degradation rate, higher levels of glycan-mature chimeric receptors, increased sensitivity to low levels of EGF (replacing EPO in this system) and extended signalling cascades. This study provides a novel experimental system to study polycythaemia-inducing mutations in the EPOR, and sheds new light on underlying mechanisms of EPOR over-activation in PFCP patients.

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Section: Discussionmentioning

confidence: 99%

“…The vast majority of these mutations result in a truncated receptor and the loss of its negative regulatory domain. (Kralovics & Prchal, 2001;O'Rourke et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Polycythaemia-inducing mutations in the erythropoietin receptor (EPOR): mechanism and function as elucidated by epidermal growth factor receptor-EPOR chimeras

et al. 2014

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Genetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases

et al. 2013

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Congenital Erythrocytosis (CE), also called 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. 3Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and generally results from mutations in the erythropoietin-receptor gene (EPOR).Secondary congenital erythrocytosis arises from conditions which cause tissue hypoxia thus resulting in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (genes HBB, HBA1 and HBA2), decreased production of 2,3-biphosphoglycerate due to mutations in the BPGM gene, 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 (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database (LOVD).

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A case of primary familial congenital polycythemia with a novel EPOR mutation: possible spontaneous remission/alleviation by menstrual bleeding

et al. 2018

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A 10-year-old girl with persistent erythrocytosis and ruddy complexion was diagnosed with primary familial congenital polycythemia (PFCP) involving a novel heterozygous mutation of c.1220C>A, p.Ser407X in exon 8 of the erythropoietin receptor gene (EPOR). This mutation causes truncation of EPOR, resulting in loss of the cytoplasmic region, which is necessary for negative regulation of erythropoietin signal transmission. Genetic analysis showed that the mutated EPOR was inherited from her mother. Her mother had polycythemia and had undergone venesection several times when she was young, but her polycythemic state appeared to have resolved. Venesection was not needed to maintain Hct levels within normal range. For the case reported here, venesection was also conducted to maintain the blood Hct level below 50%. We observed that after the patient experienced menarche, the volume and frequency of venesection needed to maintain Hct level < 50% were clearly reduced compared with those before menarche. These findings suggest that, in female patients with this type of EPOR mutation, menstruation might reduce blood volume in a manner similar to venesection. Spontaneous remission of erythrocytosis may thus occur after the start of menstrual bleeding.

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A novel mutation of the erythropoietin receptor gene associated with primary familial and congenital polycythaemia

Cited by 8 publications

References 17 publications

Polycythaemia-inducing mutations in the erythropoietin receptor (EPOR): mechanism and function as elucidated by epidermal growth factor receptor-EPOR chimeras

Polycythaemia-inducing mutations in the erythropoietin receptor (EPOR): mechanism and function as elucidated by epidermal growth factor receptor-EPOR chimeras

Genetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases

A case of primary familial congenital polycythemia with a novel EPOR mutation: possible spontaneous remission/alleviation by menstrual bleeding

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