HBG1HBG2

HBG1 and HBG2 are human genes that encode the gamma-globin chains of fetal hemoglobin (HbF). They are located on chromosome 11p15.4 and form part of the beta-like globin gene cluster, which also includes HBE1 (epsilon-globin), HBD (delta-globin), and HBB (beta-globin). HBG1 and HBG2 encode two highly related gamma-globin chains, referred to as gamma A and gamma G, respectively.

HbF, composed of two alpha and two gamma chains, is the predominant hemoglobin produced during fetal development. It has a higher affinity for oxygen than adult hemoglobin and adapts the fetal circulatory system for efficient oxygen transfer. After birth, HbF levels decline as HbA (alpha2 beta2) becomes the major adult hemoglobin. The gamma-globin genes are normally silenced in adulthood as part of a developmental switch.

Regulation of HBG1 and HBG2 involves a network of transcription factors and regulatory elements. Key regulators include BCL11A and various distal and promoter elements that repress gamma-globin expression in adult erythroid cells. Conversely, certain genetic variants and deletions can relieve repression or enhance gamma-globin transcription, leading to elevated HbF in some individuals.

Genetic variation in and around HBG1 and HBG2 influences HbF levels. Some deletions, especially hereditary persistence of fetal hemoglobin (HPFH) deletions, and promoter mutations can result in sustained HbF into adulthood. Additionally, common polymorphisms affecting HbF are found in the broader beta-like globin locus, including regulatory regions such as the BCL11A enhancer.

Clinical significance: Increased HbF through reactivation of HBG1/HBG2 can ameliorate symptoms in sickle cell disease and beta-thalassemia by reducing abnormal hemoglobin polymerization and improving oxygen transport. Therapeutic strategies often target gamma-globin reactivation via gene editing or pharmacologic approaches.