Alternative titles; symbols
DO: 0111632;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.4 | Erythrocytosis, familial, 6 | 617980 | Autosomal dominant | 3 | HBB | 141900 |
A number sign (#) is used with this entry because autosomal dominant erythrocytosis-6 (ECYT6) is caused by heterozygous mutations in the beta globin gene (HBB; 141900) that result in a high oxygen affinity hemoglobin.
Familial erythrocytosis-6 is characterized by an increased oxygen affinity of hemoglobin (Hb), which results in decreased delivery of oxygen into the peripheral tissues and compensatory polycythemia. Patients are generally asymptomatic, as compensatory polycythemia assures normal oxygen tissue delivery. Patients have normal red cell morphology (summary by Kralovics and Prchal, 2000). Wajcman and Galacteros (2005) noted that although high oxygen affinity hemoglobins are usually well tolerated in young patients, they can lead to thrombotic complications in older patients or when they are associated with another cause that increases thrombotic risk. Wajcman and Galacteros (2005) also noted that the effect of increased oxygen affinity of Hb caused by an alpha chain variant (see 617981) is usually milder than that caused by a beta chain variant.
In 4 generations of a family of English ancestry, Honig et al. (1990) found 15 persons with erythrocytosis. Elevated hemoglobin levels were accompanied by leftward-shifted whole blood oxygen equilibrium curves. Phlebotomies for relief of symptoms attributable to erythrocytosis had been necessary in 5 of the affected family members. Oxygen equilibrium curves demonstrated normal Bohr effect but decreased cooperativity.
In a Portuguese family living in Coimbra, Portugal, Tamagnini et al. (1991) identified a high oxygen affinity hemoglobin variant. Two affected members had erythrocytosis with hemoglobin levels of 18 to 20 g/dl.
Erythrocytosis caused by high oxygen affinity Hb variants is inherited in an autosomal dominant manner (Wajcman and Galacteros, 2005).
Because some high oxygen affinity hemoglobins are electrophoretically silent, the determination of hemoglobin oxygen dissociation kinetics is the best initial screening laboratory test for suspected congenital secondary polycythemia. A decreased P(50) indicates mutant hemoglobin or, even rarer, 2,3-bisphosphoglycerate deficiency (summary by Kralovics and Prchal, 2000).
The hemoglobin tetramer oscillates between the R (relaxed; fully oxygenated hemoglobin) and T (tense; fully deoxygenated hemoglobin) state of the quaternary protein conformation, requiring the cooperative interaction of globin subunits. Mutations affecting the equilibrium between R and T states result in a change of oxygen affinity. Most of these mutations occur in the alpha1/beta2 interface of the tetramer, but some interfere with the 2,3-bisphosphate binding site, and others occur at the C terminus of one of the globin subunits and interfere with binding of heme (summary by Kralovics and Prchal, 2000).
Erythrocytosis can be a feature of several variant beta globins (Weatherall, 1969); see, e.g., hemoglobins Little Rock (141900.0159), Yakima (141900.0301), Kempsey (141900.0146), Ypsilanti (141900.0307), and Hiroshima (141900.0110).
In 6 members of a Caucasian family with erythrocytosis, Stamatoyannopoulos et al. (1968) identified a high oxygen affinity hemoglobin caused by a tyr145-to-his substitution in the HBB gene (Hb Rainier; 141900.0232).
In affected individuals in a family of English ancestry with erythrocytosis, Honig et al. (1990) identified a leu105-to-phe substitution in the HBB gene (Hb South Milwaukee; 141900.0391).
In affected members of a Portuguese family with erythrocytosis, Tamagnini et al. (1991) identified a heterozygous asp99-to-glu mutation in the HBB gene (Hb Coimbra; 141900.0405).
Gonzalez Fernandez et al. (2009) noted that 89 Hb variants that show high affinity for oxygen had been described: 18 in the alpha chain and 71 in the beta chain. Two thirds of them are not accompanied by erythrocytosis either because the affinity increase is slight or moderate and only found during in vitro studies or when molecular instability is also present, determining a concomitant hemolysis; or if the mutating gene expression is low, as occurs in the alpha chain variations, or is reduced, as in Hb Crete (141900.0058).
Geary, C. G., Amos, H. E., MacIver, J. E. Benign familial polycythemia. J. Clin. Path. 20: 158-160, 1967. [PubMed: 5602507] [Full Text: https://doi.org/10.1136/jcp.20.2.158]
Gonzalez Fernandez, F. A., Villegas, A., Ropero, P., Carreno, M. D., Anguita, E., Polo, M., Pascual, A., Henandez, A. Haemoglobinopathies with high oxygen affinity: experience of erythropathology Cooperative Spanish Group. Ann. Hemat. 88: 235-238, 2009. [PubMed: 18818920] [Full Text: https://doi.org/10.1007/s00277-008-0581-x]
Honig, G. R., Vida, L. N., Latorraca, R., Divgi, A. B. Hb South Milwaukee (beta105 (G7) leu-to-phe): a newly-identified hemoglobin variant with high oxygen affinity. Am. J. Hemat. 34: 199-203, 1990. [PubMed: 2363414] [Full Text: https://doi.org/10.1002/ajh.2830340308]
Kralovics, R., Prchal, J. T. Congenital and inherited polycythemia. Curr. Opin. Pediat. 12: 29-34, 2000. [PubMed: 10676771] [Full Text: https://doi.org/10.1097/00008480-200002000-00006]
Stamatoyannopoulos, G., Yoshida, A., Adamson, J., Heinenberg, S. Hemoglobin Rainier (beta 145 tyrosine to histidine): alkali-resistant hemoglobin with increased oxygen affinity. Science 159: 741-743, 1968. [PubMed: 17795074] [Full Text: https://doi.org/10.1126/science.159.3816.741]
Tamagnini, G. P., Ribeiro, M. L., Valente, V., Ramachandran, M., Wilson, J. B., Baysal, E., Gu, L.-H., Huisman, T. H. J. Hb Coimbra or beta-99(G1)asp-to-glu, a newly discovered high oxygen affinity variant. Hemoglobin 15: 487-496, 1991. [PubMed: 1814856] [Full Text: https://doi.org/10.3109/03630269109027896]
Wajcman, H., Galacteros, F. Hemoglobins with high oxygen affinity leading to erythrocytosis: new variants and new concepts. Hemoglobin 29: 91-106, 2005. [PubMed: 15921161]
Weatherall, D. J. Polycythemia resulting from abnormal hemoglobins. New Eng. J. Med. 280: 604-606, 1969. [PubMed: 5764827] [Full Text: https://doi.org/10.1056/NEJM196903132801107]