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. 1998 Jul 1;102(1):124–129. doi: 10.1172/JCI2886

Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia.

R Kralovics 1, L Sokol 1, J T Prchal 1
PMCID: PMC509073  PMID: 9649565

Abstract

Primary 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.

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Selected References

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  1. Alfrey C. P., Rice L., Udden M. M., Driscoll T. B. Neocytolysis: physiological down-regulator of red-cell mass. Lancet. 1997 May 10;349(9062):1389–1390. doi: 10.1016/S0140-6736(96)09208-2. [DOI] [PubMed] [Google Scholar]
  2. Anagnostou A., Lee E. S., Kessimian N., Levinson R., Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5978–5982. doi: 10.1073/pnas.87.15.5978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anagnostou A., Liu Z., Steiner M., Chin K., Lee E. S., Kessimian N., Noguchi C. T. Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3974–3978. doi: 10.1073/pnas.91.9.3974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arcasoy M. O., Degar B. A., Harris K. W., Forget B. G. Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene. Blood. 1997 Jun 15;89(12):4628–4635. [PubMed] [Google Scholar]
  5. D'Andrea A. D., Yoshimura A., Youssoufian H., Zon L. I., Koo J. W., Lodish H. F. The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol. 1991 Apr;11(4):1980–1987. doi: 10.1128/mcb.11.4.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Damen J. E., Cutler R. L., Jiao H., Yi T., Krystal G. Phosphorylation of tyrosine 503 in the erythropoietin receptor (EpR) is essential for binding the P85 subunit of phosphatidylinositol (PI) 3-kinase and for EpR-associated PI 3-kinase activity. J Biol Chem. 1995 Oct 6;270(40):23402–23408. doi: 10.1074/jbc.270.40.23402. [DOI] [PubMed] [Google Scholar]
  7. Digicaylioglu M., Bichet S., Marti H. H., Wenger R. H., Rivas L. A., Bauer C., Gassmann M. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3717–3720. doi: 10.1073/pnas.92.9.3717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Emanuel P. D., Eaves C. J., Broudy V. C., Papayannopoulou T., Moore M. R., D'Andrea A. D., Prchal J. F., Eaves A. C., Prchal J. T. Familial and congenital polycythemia in three unrelated families. Blood. 1992 Jun 1;79(11):3019–3030. [PubMed] [Google Scholar]
  9. Erslev A. J., Caro J. Pure erythrocytosis classified according to erythropoietin titers. Am J Med. 1984 Jan;76(1):57–61. doi: 10.1016/0002-9343(84)90750-2. [DOI] [PubMed] [Google Scholar]
  10. Furukawa T., Narita M., Sakaue M., Otsuka T., Kuroha T., Masuko M., Azegami T., Kishi K., Takahashi M., Utsumi J. Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor. Br J Haematol. 1997 Oct;99(1):222–227. doi: 10.1046/j.1365-2141.1997.3583172.x. [DOI] [PubMed] [Google Scholar]
  11. Goldwasser E., Sherwood J. B. Radioimmunoassay of erythropoietin. Br J Haematol. 1981 Jul;48(3):359–363. doi: 10.1111/j.1365-2141.1981.tb02726.x. [DOI] [PubMed] [Google Scholar]
  12. Gregory C. J., Eaves A. C. Human marrow cells capable of erythropoietic differentiation in vitro: definition of three erythroid colony responses. Blood. 1977 Jun;49(6):855–864. [PubMed] [Google Scholar]
  13. Juvonen E., Ikkala E., Fyhrquist F., Ruutu T. Autosomal dominant erythrocytosis caused by increased sensitivity to erythropoietin. Blood. 1991 Dec 1;78(11):3066–3069. [PubMed] [Google Scholar]
  14. Kan Y. W., Dozy A. M. Polymorphism of DNA sequence adjacent to human beta-globin structural gene: relationship to sickle mutation. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5631–5635. doi: 10.1073/pnas.75.11.5631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klingmüller U., Lorenz U., Cantley L. C., Neel B. G., Lodish H. F. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 1995 Mar 10;80(5):729–738. doi: 10.1016/0092-8674(95)90351-8. [DOI] [PubMed] [Google Scholar]
  16. Kralovics R., Indrak K., Stopka T., Berman B. W., Prchal J. F., Prchal J. T. Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias. Blood. 1997 Sep 1;90(5):2057–2061. [PubMed] [Google Scholar]
  17. Kralovics R., Sokol L., Broxson E. H., Jr, Prchal J. T. The erythropoietin receptor gene is not linked with the polycythemia phenotype in a family with autosomal dominant primary polycythemia. Proc Assoc Am Physicians. 1997 Nov;109(6):580–585. [PubMed] [Google Scholar]
  18. Le Couedic J. P., Mitjavila M. T., Villeval J. L., Feger F., Gobert S., Mayeux P., Casadevall N., Vainchenker W. Missense mutation of the erythropoietin receptor is a rare event in human erythroid malignancies. Blood. 1996 Feb 15;87(4):1502–1511. [PubMed] [Google Scholar]
  19. Masuda S., Nagao M., Takahata K., Konishi Y., Gallyas F., Jr, Tabira T., Sasaki R. Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem. 1993 May 25;268(15):11208–11216. [PubMed] [Google Scholar]
  20. Percy M. J., McMullin M. F., Roques A. W., Westwood N. B., Acharya J., Hughes A. E., Lappin T. R., Pearson T. C. Erythrocytosis due to a mutation in the erythropoietin receptor gene. Br J Haematol. 1998 Feb;100(2):407–410. doi: 10.1046/j.1365-2141.1998.00550.x. [DOI] [PubMed] [Google Scholar]
  21. Prchal J. T., Crist W. M., Goldwasser E., Perrine G., Prchal J. F. Autosomal dominant polycythemia. Blood. 1985 Nov;66(5):1208–1214. [PubMed] [Google Scholar]
  22. Sheffield V. C., Beck J. S., Kwitek A. E., Sandstrom D. W., Stone E. M. The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics. 1993 May;16(2):325–332. doi: 10.1006/geno.1993.1193. [DOI] [PubMed] [Google Scholar]
  23. Shultz L. D., Schweitzer P. A., Rajan T. V., Yi T., Ihle J. N., Matthews R. J., Thomas M. L., Beier D. R. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell. 1993 Jul 2;73(7):1445–1454. doi: 10.1016/0092-8674(93)90369-2. [DOI] [PubMed] [Google Scholar]
  24. Sokol L., Luhovy M., Guan Y., Prchal J. F., Semenza G. L., Prchal J. T. Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin. Blood. 1995 Jul 1;86(1):15–22. [PubMed] [Google Scholar]
  25. Sokol L., Prchal J. F., D'Andrea A., Rado T. A., Prchal J. T. Mutation in the negative regulatory element of the erythropoietin receptor gene in a case of sporadic primary polycythemia. Exp Hematol. 1994 May;22(5):447–453. [PubMed] [Google Scholar]
  26. Sokol L., Prchal J. T. Two microsatellite repeat polymorphisms in the EPO gene. Hum Mol Genet. 1994 Jan;3(1):219–219. doi: 10.1093/hmg/3.1.219. [DOI] [PubMed] [Google Scholar]
  27. Sokol L., Prchal J., Prchal J. T. Primary familial and congenital polycythaemia. Lancet. 1993 Jul 10;342(8863):115–116. doi: 10.1016/0140-6736(93)91317-f. [DOI] [PubMed] [Google Scholar]
  28. Songyang Z., Shoelson S. E., Chaudhuri M., Gish G., Pawson T., Haser W. G., King F., Roberts T., Ratnofsky S., Lechleider R. J. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993 Mar 12;72(5):767–778. doi: 10.1016/0092-8674(93)90404-e. [DOI] [PubMed] [Google Scholar]
  29. Tauchi T., Feng G. S., Shen R., Hoatlin M., Bagby G. C., Jr, Kabat D., Lu L., Broxmeyer H. E. Involvement of SH2-containing phosphotyrosine phosphatase Syp in erythropoietin receptor signal transduction pathways. J Biol Chem. 1995 Mar 10;270(10):5631–5635. doi: 10.1074/jbc.270.10.5631. [DOI] [PubMed] [Google Scholar]
  30. de la Chapelle A., Sistonen P., Lehväslaiho H., Ikkala E., Juvonen E. Familial erythrocytosis genetically linked to erythropoietin receptor gene. Lancet. 1993 Jan 9;341(8837):82–84. doi: 10.1016/0140-6736(93)92558-b. [DOI] [PubMed] [Google Scholar]
  31. de la Chapelle A., Träskelin A. L., Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4495–4499. doi: 10.1073/pnas.90.10.4495. [DOI] [PMC free article] [PubMed] [Google Scholar]

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