Four hemoglobin variants had previously been described that involve the first codon of the HBB gene: Hb Doha (141900.0069), Hb South Florida (141900.0266), Hb Niigata (141900.0471), and Hb Raleigh (141900.0233). Although none of these variants cause any significant clinical problems, mutations of the first codon are of interest because of their potential interference with cotranslational modification at this site during beta-globin synthesis. In eukaryotes, the translation of all peptide mRNAs starts at an AUG codon, producing methionine at the beginning of the nascent peptide chain. In most proteins, including alpha-, beta-, and gamma-globin, this methionine is cotranslationally cleaved when the chain is 20 to 30 amino acids long. This results in the first amino acid being valine in alpha-, beta-, and delta-globin, and glycine in gamma-globin. When the peptide chain is 40 to 50 amino acids long, further modification occurs with acetylation at the NH2-terminal residue. The extent of the acetylation depends on the identity of the N-terminal amino acid; valine is strongly inhibitory to this process, leading to little acetylation of alpha- and beta-globin. However, the N-terminal glycine of gamma-globin is less inhibitory, resulting in about 15% acetylation. Fisher et al. (2000) identified a new Hb variant, Hb Watford, in which a GTG-to-GGG substitution caused a change of the first amino acid of the beta-globin chain from methionine to glycine, mimicking the gamma-globin chain. The proband was a 48-year-old female of Jewish extraction who was evaluated for chronic mild anemia. Another mutation was found in cis with the val1-to-gly mutation: Cap+36G-A.
