Inclusion body ß-thalassemia trait in a Swiss family is caused by an abnormal hemoglobin (Geneva) with an altered and extended ß chain carboxy-terminus due to a modification in codon ß114

We have analyzed the sequence of the ß globin gene of a chromosome that is linked to the occurrence of an inclusion body ß-thalassemia characterized in the heterozygote by moderate anemia, severe red cell abnormalities, splenomegaly, inclusion body formation, elevated Hb A₂ levels, and an increased in vitro a/ß chain synthetic ratio. The data indicate a change in codon 114 from CTG (Leu) to -GG that resulted in a frameshift and the presumed synthesis of an abnormal ß chain that is 156 residues long with a completely different C-terminal amino acid sequence. The change in codon 114 gives a -GGGCCC- sequence that creates a new ApaI site; the resulting 2.6-kilobase fragment has been observed in all subjects with this thalassemia condition. Protein structural analyses failed to demonstrate any trace of the abnormal ß chain, even in reticulocytes and nucleated red cells that were isolated by density gradient centrifugation. The inclusion bodies appear to contain mainly normal a chains. It is assumed that the structure of the ß-Geneva chain prevents it from combining with normal a chains; this results in a rapid breakdown of the abnormal protein during the early stages of red cell maturation and an accumulation of free a chains.