The dominant beta-thalassaemia in a Spanish family is due to a frameshift that introduces an extra CGG codon ( = arginine) at the 5' end of the second exon

Abstract

We have discovered a Spanish family with a dominant type of beta-thalassaemia. Carriers are characterized by mild anaemia, hypochromia, microcytosis, elevated Hb A2 and Hb F levels, reticulocytosis, and splenomegaly. The molecular basis of this condition is the introduction of a CGG triplet between codons 30 and 31 of the beta gene; this was determined by sequencing of amplified DNA and confirmed by dot-blot analysis. The abnormal mRNA (beta Th-mRNA) is stable and present in quantities similar to that of normal beta A-mRNA. cDNA fragments derived from beta Th- and beta A-mRNAs can be separated on a denaturing polyacrylamide gel electrophoresis because the beta Th fragment is three nucleotides (nts) longer than the beta A fragment. The beta Th-mRNA translates into a beta chain that is 147 amino acid residues long and carries an extra arginine residue between residues 30 and 31. This beta X chain has not been detected. It may be unstable and does not bind to the alpha chain. It probably is continuously digested by proteolytic enzymes in red cell precursors in the bone marrow. The abnormal chain probably binds haem that is excreted after proteolysis causing a darkening of the urine.