HBG1 (hemoglobin subunit gamma 1; HGNC:4831, NCBI Gene ID 3047) is a human locus mapped to chromosome band 11p15.4 that encodes A-gamma-globin polypeptide chain (146 aa; carries Alanine at residue 136). HBG1 acts in fetal hemoglobin (HbF, alpha2-gamma2) oxygen transport & adult BCL11A repression, together with HBG2 (G-Gamma Fetal Globin Gene), HBB (Adult Beta-Globin Gene), and BCL11A (Fetal Hemoglobin Repressor Gene). Encodes the A-gamma globin chain of fetal hemoglobin (HbF), whose reactivation rescues sickle cell disease and beta-thalassemia.
Approved Symbol
HBG1
Chromosomal Locus
11p15.4
Encoded Product
A-gamma-globin polypeptide chain (146 aa; carries Alanine at residue 136)
Primary Pathway
Fetal hemoglobin (HbF, alpha2-gamma2) oxygen transport & adult BCL11A repression
Clinical / Therapeutic Role
Promoter variants cause Hereditary Persistence of Fetal Hemoglobin (HPFH); reactivated by Casgevy CRISPR editing in SCD & beta-thalassemia
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 3-exon gene located within the beta-globin locus control region (LCR) cluster on chromosome 11p15.4 (5-prime—HBE1—HBG2—HBG1—HBD—HBB—3-prime), arising from a tandem 5 kb duplication alongside HBG2 and distinguished only by encoding alanine (rather than glycine) at codon 136.
Cellular & Tissue Expression Profile: Maximally transcribed in fetal liver and bone marrow erythroblasts from 8 weeks of gestation until birth, after which adult erythroid transcription factors BCL11A and ZBTB7A (LRF) bind the -115 bp and -200 bp promoter motifs of HBG1 and HBG2 to silence gamma-globin and switch expression to adult beta-globin (HBB).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Two gamma-globin chains pair with two alpha-globin chains and four heme prosthetic groups to form fetal hemoglobin (HbF, alpha2-gamma2), which binds 2,3-bisphosphoglycerate less avidly than adult HbA (due to Ser143 replacing His143), conferring higher oxygen affinity to extract O2 across the placenta while sterically blocking the polymerization of deoxygenated sickle hemoglobin (HbS).
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Naturally occurring point mutations in the HBG1/HBG2 proximal promoter (such as -117G>A, -114C>T, and -198T>C) disrupt BCL11A or ZBTB7A repressor binding and cause benign Hereditary Persistence of Fetal Hemoglobin (HPFH), which completely prevents vaso-occlusive crises and anemia when co-inherited with sickle cell disease or beta-thalassemia.
Therapeutic & Clinical Pharmacology: Reactivated clinically by hydroxyurea, by exagamglogene autotemcel (Casgevy, which disrupts the erythroid BCL11A enhancer), and by direct CRISPR-Cas9/Cas12a or base-editing disruption of the BCL11A binding site within the HBG1 and HBG2 promoters (such as renizgamglogene autogedtemcel / BEAM-101).