ChatNewborn babies are naturally protected from sickle cell anemia because they produce healthy fetal hemoglobin; an obscure genetic repressor called BCL11A shuts off this baby blood switch a few months after birth. Discovered in 2008 by Stuart Orkin and Swee Lay Thein, BCL11A became the exact genetic target for Casgevy—the world’s first FDA-approved CRISPR gene-editing medicine that cures sickle cell disease.
Sickle cell disease causes red blood cells to deform into stiff, sickle-shaped crescents that block blood vessels, causing excruciating pain crises and early organ failure. For a century, doctors noticed a curious medical miracle: newborn infants with the sickle mutation show zero symptoms because their bodies are still making fetal hemoglobin, which never sickles.
Geneticists hunted for the biological off-switch that shuts down fetal hemoglobin after birth. They discovered a master repressor gene called BCL11A. Acting like a genetic dimmer switch, BCL11A turns off healthy fetal blood production at six months of age, forcing the body to produce defective adult sickle cells.
By disabling the BCL11A switch with CRISPR gene-editing scissors, doctors turn fetal blood production back on permanently. By eliminating excruciating pain crises in sickle cell patients, by freeing patients from lifelong blood transfusions, and by delivering the first commercial CRISPR cure in history (Casgevy), BCL11A biology cures genetic disease.
Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia
beta-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait (P < 10(-35)). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for beta-thalassemia, and patients with attenuated forms of beta-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the beta-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for beta-thalassemia and sickle cell anemia.
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