Autosomal dominant erythrocytosis caused by increased sensitivity to erythropoietin

Juvonen, Eeva; Ikkala, Esko; Fyhrquist, F; Ruutu, Tapani

doi:10.1182/blood.v78.11.3066.bloodjournal78113066

Cited by 31 publications

(42 citation statements)

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“…The cells from Granulocyte-Macrophage Colony Forming Unit (CFU-GM), Granulocyte-CFU (CFU-G), Macrophage-CFU (CFU-M), and erythroid-burst forming units (BFU-E) colonies were obtained from the in vitro cultures of normal human bone marrow mononuclear cells (MNC) cultured for routine purposes as previously described (Juvonen et al, 1991). The CFU-GM, CFU-G, CFU-M or BFU-E colonies were identified by inversion microscopy, based on the typical morphology or red colour of the cells, respectively.…”

Section: Methodsmentioning

confidence: 99%

Podocalyxin in human haematopoietic cells

Kerosuo

Juvonen²,

Alitalo

et al. 2004

Br J Haematol

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Summary Podocalyxin‐like protein (PCLP) is a sialomucin‐type membrane protein structurally related to CD34 and endoglycan. It was first described in glomerular podocytes and endothelial cells. In mice, PCLP is present in haemangioblasts, and in both chicken and mice it is a marker of early haematopoietic stem cells and lineage‐restricted haematopoietic progenitors. Its expression decreases during differentiation of haematopoietic cells. Of mature blood cells, only chicken and rat thrombocytes express PCLP protein. PCLP expression in human haematopoietic cells has not been studied. Here we demonstrate PCLP mRNA in human CD34+ cells, in lineage committed erythroid, megakaryocyte and myeloid progenitors, in K562 leukaemia cells, and in peripheral blood leucocytes. The mRNA expression level was higher in developing cells than in mature leucocytes. By Northern blotting and cDNA sequencing, the haematopoietic and renal PCLP mRNAs were identical. Of the mobilized CD34+ cells, 28% (mean; range 14–61%) expressed PCLP protein and the majority of PCLP+ cells were CD117+. Almost all of the K562 cells expressed PCLP protein. Surprisingly, PCLP protein was not detected in any mature blood cells. These results suggest that human PCLP may be a valuable marker for a subset of haematopoietic stem cells.

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Section: Methodsmentioning

confidence: 99%

Podocalyxin in human haematopoietic cells

Kerosuo

Juvonen²,

Alitalo

et al. 2004

Br J Haematol

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“…Recent experiments have demonstrated that both tyrosines are responsible for binding of SHIP-1 to EpoR (Yi et al, 1995). Primer positions are also indicated by the arrows in the figure. these patients to erythropoietin, which has been demonstrated at low Epo levels in other PFCP families (Prchal et al, 1985;Juvonen et al, 1991;Sokol et al, 1995).…”

Section: Study Of Erythroid Progenitorsmentioning

confidence: 58%

“…Affected family members do not usually need any specific treatment for their polycythaemia and their degree of erythrocytosis has remained remarkably stable (Prchal et al, 1985;Emanuel et al, 1992). In vitro cultures have demonstrated an increased sensitivity of erythroid progenitors from these family members, although no erythroid colonies formed in cultures without erythropoietin (Epo) ( Juvonen et al, 1991;Sokol et al, 1995). Erythrocytosis in these families has been demonstrated to be significantly linked with erythropoietin receptors (EpoR), via the detection of a simple sequence repeat polymorphism in the EpoR (Sokol et al, 1993Chapelle et al, 1993a).…”

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confidence: 99%

Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor

et al. 1997

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Primary familial and congenital polycythaemia (PFCP) is a rare disease characterized by congenital erythrocytosis inherited in an autosomal dominant fashion. Recently, mutations in the erythropoietin receptor (EpoR) have been identified in PFCP families. We describe a Japanese family with an autosomal dominant inheritance of PFCP. An in vitro colony assay demonstrated hypersensitivity of erythroid progenitors to erythropoietin (Epo) in affected family members. Sequence analysis of RT‐PCR products amplified from the C‐terminal region of EpoR transcripts in affected family members revealed that they were all heterozygous for C and T bases at position 5986, which suggested a genetic mutation (C to T) on one allele of EpoR. This mutation gave rise to a translation termination codon TAG at amino acid 435. Thus, the resulting EpoR is a truncated protein product lacking all 74 amino acids downstream of the mutation. To date, all genetic mutations affecting a family with PFCP, including this one, have been located in the cytoplasmic negative regulatory region of the EpoR. All mutations gave rise to truncated Epo receptors between Tyrosine 427 and Tyrosine 455. The phosphotyrosines in this region of EpoR have been demonstrated to be binding sites for SHP‐1 phosphatase. Therefore PFCP is presumably brought about as a result of genetic mutations which cause the loss of the SHP‐1 binding site in the cytoplasmic region of EpoR.

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“…A cross-country skier who won several Olympic gold medals was initially accused of doping. However, it was later determined that he had an autosomal dominant mutation in his EPO receptor resulting in erythrocytosis and haematocrit levels up to 68% (Prchal et al, 1985;Juvonen et al, 1991) (for comparison, the normal haematocrit range is 39-45%). Considerations must be made to avoid inappropriate sanctioning of athletes who, through genetics or physiology, test positive for doping.…”

Section: Testing Strategiesmentioning

confidence: 99%

Erythropoiesis‐stimulating agents and other methods to enhance oxygen transport

Elliott

2008

British J Pharmacology

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Oxygen is essential for life, and the body has developed an exquisite method to collect oxygen in the lungs and transport it to the tissues. Hb contained within red blood cells (RBCs), is the key oxygen-carrying component in blood, and levels of RBCs are tightly controlled according to demand for oxygen. The availability of oxygen plays a critical role in athletic performance, and agents that enhance oxygen delivery to tissues increase aerobic power. Early methods to increase oxygen delivery included training at altitude, and later, transfusion of packed RBCs. A breakthrough in understanding how RBC formation is controlled included the discovery of erythropoietin (Epo) and cloning of the EPO gene. Cloning of the EPO gene was followed by commercial development of recombinant human Epo (rHuEpo). Legitimate use of this and other agents that affect oxygen delivery is important in the treatment of anaemia (low Hb levels) in patients with chronic kidney disease or in cancer patients with chemotherapy-induced anaemia. However, competitive sports was affected by illicit use of rHuEpo to enhance performance. Testing methods for these agents resulted in a cat-and-mouse game, with testing labs attempting to detect the use of a drug or blood product to improve athletic performance (doping) and certain athletes developing methods to use the agents without being detected. This article examines the current methods to enhance aerobic performance and the methods to detect illicit use.

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Autosomal dominant erythrocytosis caused by increased sensitivity to erythropoietin

Cited by 31 publications

References 0 publications

Podocalyxin in human haematopoietic cells

Podocalyxin in human haematopoietic cells

Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor

Erythropoiesis‐stimulating agents and other methods to enhance oxygen transport

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