In a typical beta-thalassemia (613985) carrier of Italian descent, Saba et al. (1992) demonstrated a G-to-A transition in the initiation codon of the HBB gene, producing a substitution of isoleucine for methionine. The absence of the initiation methionine led to defective beta-globin mRNA translation and probably determined the complete absence of beta-chain production. Indeed, initiation of translation may have occurred at the first downstream ATG sequence, which is located at codon 21-22; the resulting out-of-frame reading probably terminates at the new UGA termination codon at codon 60-61. Initiation codon mutations previously described in both the alpha (141850.0022) and beta (141900.0344) globin genes all result in complete inactivation of the affected globin gene.
In 7 members of 3 generations of a family living in northern Sweden, Landin et al. (1995) found an initiation codon mutation ATG-to-ATA of the HBB gene. The mutation changed the initiation codon from methionine to isoleucine and resulted in a beta-zero-thalassemic phenotype. The affected family members all presented hematologic findings typical for the beta-thalassemic trait, with slight anemia, marked microcytosis, and increased levels of Hb A2. See 141900.0345 for an initiation codon mutation ATG-to-ACG, which changes methionine to threonine.
