Genetic mechanisms underlying regulation of hemoglobin mass

Hemoglobin, the sole carrier of oxygen to tissues, accounts for most cytoplasmic protein of the erythrocyte, an enucleate cell lacking protein synthesizing machinery and with limited energy metabolism. While a number of genetic mechanisms can result in decreased hemoglobin concentration in the blood, this review concentrates on those that lead to increased hemoglobin mass, i.e. polycythemia or erythrocytosis. Polycythemia may be due to (a) mutations of the enzyme synthesizing 2, 3 BPG, a metabolic intermediate which regulates hemoglobin-oxygen affinity and thus oxygen delivery, (b) mutation of the alpha or beta globin genes that increase hemoglobin-oxygen affinity and thus decrease oxygen delivery, and (c) mutations of the erythropoietin receptor gene or genes regulating erythropoietin production that lead to increased production of erythrocytes. Primary polycythemias are caused by inherited or acquired somatic mutations affecting the hematopoietic progenitors. In contrast, in secondary polycythemia normal progenitors are activated by external factors present in increased concentration, most commonly erythropoietin. Some hypoxia sensing disorders blur the distinction between primary and secondary polycythemias and may deserve their own category. Most polycythemias are acquired, but both primary and secondary polycythemias may be inherited. In this review we will discuss the genetic heterogeneity of individual responses to hypoxia, and the current understanding of inherited primary and secondary polycythemias.