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Two unstable hemoglobins (Hbs) causing rather severe hemolytic anemia have been characterized. The beta chain of Hb Birmingham, found in an adult black man, is characterized by the loss of -Leu-Ala-His-Lys- at positions 141, 142, 143, and 144 and their replacement by one Gln residue. These changes are the result of a deletion of nine nucleotides, namely two base pairs (bp) of codon 141, all of codons 142 and 143, and one bp of codon 144; the remaining CAG triplet (C from codon 141 and AG from codon 144) codes for the inserted glutamine. In the beta chain of Hb Galicia from a Spanish patient, His and Val at positions 97 and 98 are replaced by one Leu residue. This is due to an ACG deletion in codons 97 and 98, which causes the removal of one His and one Val residue, while the remaining CTG triplet (C from codon 97 and TG from codon 98) codes for the inserted leucine residue. Two mechanisms, namely slipped mispairing in the presence of short repeats, and misreading by DNA polymerase due to a local distortion of the DNA helix, are considered in explaining the origin of the small deletions.

The unstable hemoglobin Montreal with a deletion of three amino acid residues (Asp, Gly, Leu) at positions 73, 74, and 75 of the beta chain and an insertion of four residues (Ala, Arg, Cys, Gln) at the same location was observed in a 7-year-old Canadian boy suffering from a moderate hemolytic anemia. The introduction of an extra amino acid residue and of other changes in the crevice where the heme group is located is the likely cause of the instability of this hemoglobin variant. The above listed changes were detected through analyses of tryptic peptides of the beta-Montreal chain, sequencing of amplified DNA, and hybridization of amplified DNA with appropriate, 32P-labeled, oligonucleotide probes. It is suggested that a mispairing involving the AGTG sequences at codons 66 and 67 and at codons 72 and 73 of the normal beta gene caused a repetition of a 16-bp segment, while a deletion of 10 nucleotides due to recombination or slippage followed by a second short deletion during DNA repair resulted in the modified sequence of the beta-Montreal gene.