Erythropoietin Receptor Mutations Associated With Familial Erythrocytosis Cause Hypersensitivity to Erythropoietin in the Heterozygous State

Abstract

Inherited mutations in the erythropoietin receptor (EPOR) causing premature termination of the receptor cytoplasmic region are associated with dominant familial erythrocytosis (FE), a benign clinical condition characterized by hypersensitivity of erythroid progenitor cells to EPO and low serum EPO (S-EPO) levels. We describe a Swedish family with dominant FE in which erythrocytosis segregates with a new truncation in the negative control domain of the EPOR. We show that cells engineered to concomitantly express the wild-type (WT) EPOR and mutant EPORs associated with FE (FE EPORs) are hypersensitive to EPO-stimulated proliferation and activation of Jak2 and Stat5. These results demonstrate that FE is caused by hyperresponsiveness of receptor-mediated signaling pathways and that this is dominant with respect to WT EPOR signaling.

Erythropoietin receptor defect: a cause of primary polycythaemia

“…Primary familial and congenital polycythaemia (PFCP) is a rare autosomal dominant inherited disorder with isolated proliferation of the erythroid progenitor cells leading to erythrocytosis. Patients may suffer from headaches, hypertension, dizziness, nose bleeds and pruritus after bathing (Arcasoy et al , 2002; Watowich et al , 1999). Although not formally investigated, an increased risk of both haemorrhagic and thrombotic episodes may be expected.…”

Genetic heterogeneity of primary familial and congenital polycythemia

“…SHP-1 binding to phosphorylated tyrosine 430 (analogous to murine 429) dephosphorylates a number of cytoplasmic substrates (including JAK2 kinase and STAT5), leading to the termination of the proliferative signal. This lack of (likely SHP-1 mediated) negative regulation of EPOR signaling results in prolonged STAT5 and JAK2 activation observed in cell lines expressing truncated EPORs [14,16,25]. In addition, the first intronic mutation/polymorphism (A2706T in intron IV) of the EPOR gene is reported.…”

“…PFCP is characterized by elevated hemoglobin concentration, low or normal serum erythropoietin level, hypersensitivity of erythroid progenitors to erythropoietin in vitro, normal oxygen affinity of hemoglobin, absence of progression to leukemia, and typically autosomal dominant inheritance (rarely sporadic occurrence) [1][2][3]. Abnormalities of the erythropoietin receptor (EPOR) gene were suspected to be involved in the pathogenesis of the disease, and 10 mutations in the cytoplasmic portion of the EPOR have been identified in patients with PFCP so far [4][5][6][7][8][9][10][11][12][13][14]. Eight of these mutations result in truncated EPORs lacking the cytoplasmic COOH-terminal of the receptor, whereas the remaining two missense mutations could not be demonstrated to be causative of PFCP.…”

“…The COOH-terminal of the EPOR contains a negative regulatory domain and is essential in SHP-1 phosphatase binding (a negative regulator of EPOR signaling) [15,16]. The lack of down-regulation of the EPOR after ligand binding results in increased proliferation of cells expressing these abnormal receptors [6,10,14], and it is thought to be responsible for the EPO hypersensitivity of erythroid progenitors observed in vitro in PFCP subjects [6,10,17]. It has been assumed that EPOR mutations are the major lesion responsible for this disease, although there is some evidence for exceptions [18,19].…”

Increased cell surface expression of C‐terminal truncated erythropoietin receptors in polycythemia

“…Increased EPO‐responsiveness of erythroid progenitor cells from affected individuals has been observed in semisolid culture experiments (4–6). Furthermore, in a number of cases ectopic expression of EPOR‐TTC(PFCP) in IL‐3‐dependent cell lines rendered such cells more sensitive to EPO than were cells expressing EPOR‐F (5–9).…”