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How Infancy Can Affect Sickle Cell Disease

How Infancy Can Affect Sickle Cell Disease

Hemoglobin[1] is made up of two pairs of protein subunits: two subunits of α-globin and two subunits of β-globin. α-globin is coded by two nearly identical genes, called hemoglobin subunit alpha 1 (HBA1) and hemoglobin subunit alpha 2 (HBA2), both of which are found close together in chromosome 16. β-globin is coded by the hemoglobin subunit beta, or beta globin, gene (HBB gene), found in chromosome 11.

The human β-globin locus is developmentally regulated, and leads to the production of several forms of β-globin during different stages of infancy, as shown in the following figure 1.

Figure 1 (Sankaran and Orkin): Graphical representation of human hemoglobin production starting from the embryonic stage to the post-natal stage

 

Early in the first trimester, an embryonic form of β-globin is dominant, known as  ε-globin, but quickly subsides before the second trimester begins. In its place enters the production of γ-globin, and due to its predominance in utero, two trends are observable in fetal hemoglobin: the prevalence of hemoglobin F (Hb F), which is composed of two γ-chains that combine with two α-chains, and the scarcity of hemoglobin A (Hb A), which is composed of two pairs of α- and β-chains. Soon after birth, a steep decline in γ-chain production, coupled with an increase in β-chain production, is observed. This trend tends to persist until the end of infancy, and reverses the trends found in fetal hemoglobin. In human adults, two observable trends have been noted: the predominance of Hb A, due to the robust production of both of its constituent chains after birth, and the scarcity of Hb F, due to the declining production of γ-chains after birth.

What causes the synthesis of these globin chains to be developmentally regulated is a complex system of silencing that halts the production of the γ-chain, and in return, stimulates the production of the β-chain. According to Sankaran and Orkin, the γ-globin genes undergo DNA methylation when they are silenced in adult red-blood progenitor cells, but do not when they are transcriptionally active in fetal red-blood progenitor cells.

Moreover, the production of Hb F has been shown to reduce the severity of various disorders of β-hemoglobin, primarily sickle cell disease (and other disorders like β-thalassemia). In a 1948 study on fetal hemoglobin conducted by Janet Watson, 84 to 100% of the red cells of mothers with the sickle cell trait demonstrated the usual deleterious clumping effect of sickle cells, known as “sickling,” while the red blood cells of newborns only showed 0.5 to 29.5% sickling. The large difference was attributed to the chemical difference between fetal and adult hemoglobin—the presence of Hb F. Hb F, Watson noted, is “unable to sickle even at the low oxygen tension which exists in the fetus.” Other studies have corroborated the protective influence of Hb F by investigating patients who had the sickle cell trait, as well as the rare mutation that caused the persistence of Hb F beyond infancy (known as hereditary persistence of fetal hemoglobin [HPFH]). These patients, like the infants in Watson’s study, were largely asymptomatic, and demonstrated a higher resistance against sickling.

Considering the benefits conferred by HbF, scientists have avidly pursued testing of the molecule 5-azacytidine, a known DNA methylation inhibitor. The molecule was tested, and demonstrated the potential to induce the silenced γ-globin genes and stimulate production of HbF in adults who are afflicted by disorders of β-hemoglobin.

 

Works Cited

Barrett, Julia. “Sickle Cell Anemia.” The Gale Encyclopedia of Science, edited by K. Lee Lerner and Brenda Wilmoth Lerner, 5th ed., Gale, Farmington Hills, MI, 2014. Gale In Context: Science.

“HBA1 Gene.” U.S. National Library of Medicine, National Institutes of Health, 15 Apr. 2020, ghr.nlm.nih.gov/gene/HBA1#normalfunction.

“HBA2 Gene.” U.S. National Library of Medicine, National Institutes of Health, 15 Apr. 2020, ghr.nlm.nih.gov/gene/HBA2#normalfunction.

“HBB Gene.” U.S. National Library of Medicine, National Institutes of Health, 15 Apr. 2020, ghr.nlm.nih.gov/gene/HBB#normalfunction.

Sankaran, Vijay G., and Stuart H. Orkin. “The Switch from Fetal to Adult Hemoglobin.” Cold Spring Harbor Perspectives in Medicine 3, no. 1 (January 2013). https://doi.org/10.1101/cshperspect.a011643.

Spain, David M., Victoria A. Bradess, and Irving J. Greenblatt. “Gamma Globulin Deficiency in Infancy.” Annals of the New York Academy of Sciences 66, no. 1 (1956): 176–80. https://doi.org/10.1111/j.1749-6632.1956.tb40117.x.

Watson, Janet, et al. “THE SIGNIFICANCE OF THE PAUCITY OF SICKLE CELLS IN NEWBORN NEGRO INFANTS”. The American Journal of the Medical Sciences, vol. 215, no. 4, April 1948, pp. 419-423.