MOLECULAR-BASIS OF BETA-THALASSEMIA IN JAPAN - HETEROGENEITY AND ORIGINS OF MUTATIONS

Characterization of beta-thalassemia mutations was attempted for 13 un related Japanese patients heterozygous for beta-thalassemia. We have s ystematically analyzed beta-thalassemia genes using polymerase-chain-r eaction-related techniques; dot blot hybridization with oligonucleotid e probes complementary to known mutations, restriction endonuclease as say and direct sequencing of amplified genomic DNA. Seven different mu tations were detected. Six of them are an amber mutation in codon 90 ( GAG to TAG), a four-base-pair deletion in codons 41 and 42 causing pre mature termination due to frameshift, a C-T substitution at position 6 54 of IVS-2 a G-A substitution at position 1 of IVS-2 and a C-G substi tution at position 848 of IVS-2, leading to splicing defects, and an o cher mutation (GAA-TAA) in codon 121 causing a thalassemia intermedia phenotype with inclusion body formation in erythrocytes. A silent muta tion (CTG-TTG) was also detected in codon 91 of the allele with the IV S-2 position 1 mutation. These mutations have been reported previously in the Japanese population. The other mutation is a novel one in the Japanese, an amber mutation (TGG-TAG) in codon 15, causing a beta(0)-t halassemia phenotype by premature termination of the beta-globin chain synthesis. We analyzed haplotypes of chromosomes bearing each beta-th alassemia mutation. Origins and a spectrum of mutations in comparison with those detected in malaria-endemic regions are discussed.