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

Mor Gross, Nathalie Ben-Califa, Mary F McMullin, Melanie J Percy, Celeste Bento, Holger Cario, Milen Minkov, Drorit Neumann

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Primary 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.
Original languageEnglish
Pages (from-to)519-528
Number of pages10
JournalBritish Journal of Haematology
Volume165
Issue number4
Early online date18 Feb 2014
DOIs
Publication statusPublished - May 2014

Bibliographical note

© 2014 John Wiley & Sons Ltd.

ASJC Scopus subject areas

  • Hematology

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