Inclusion Body β-Thalassemia Trait in a Swiss Family Is Caused by an Abnormal Hemoglobin (Geneva) With an Altered and Extended β Chain Carboxy-Terminus due to a Modification in Codon β114

We have analyzed the sequence of the β globin gene of a chromosome that is linked to the occurrence of an inclusion body β-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 α/β 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 β 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 Apal 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 β chain, even in reticulocytes and nucleated red cells that were isolated by density gradient centrifugation. The inclusion bodies appear to contain mainly normal α chains. It is assumed that the structure of the β-Geneva chain prevents it from combining with normal α 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. © 1988 by Grune & Stratton, Inc.