HETEROZYGOSITY FOR THE IVS-I-5 (G-]C) MUTATION WITH A G-]A CHANGE AT CODON-18 (VAL-]MET, HB BADEN) INCIS AND A T-]G MUTATION AT CODON-126 (VAL-]GLY, HB DHONBURI) INTRANS RESULTING IN A THALASSEMIA-INTERMEDIA

We have analyzed the hemoglobins of a young German patient with beta-thalassemia intermedia and of his immediate family and included in these studies an evaluation of possible nucleotide changes in the beta-globin genes through sequencing of amplified DNA. One chromosome of the propositus and one of his father's carried the GTG --> GGG mutation at codon 126 leading to the synthesis of Hb Dhonburi or alpha2beta2126(H4)Val --> Gly; this variant is slightly unstable and is associated with mild thalassemic features. His second chromosome and one of his mother's had the common IVS-I-5 (G --> C) mutation that leads to a rather severe beta+-thalassemia and the GTG --> ATG mutation at codon 18, resulting in the replacement of a valine residue by a methionine residue. This newly discovered beta-chain variant, named Hb Baden, was present for only 2-3% in both the patient and his mother. This low amount results from a decreased splicing of RNA at the donor splice-site of the first intron that is nearly completely deactivated by the IVS-1-5 (G --> C) thalassemic mutation. The chromosome with the codon 18 (GTG --> ATG) and the IVS-I-5 (G --> C) mutations has thus far been found only in this German family; analysis of 51 chromosomes from patients with the IVS-1-5 (G --> C) mutation living in different countries failed to detect the codon 18 (GTG --> ATG) change.