Sardinian Haplotype II β0-Thalassemia Is Linked to the Variant AγT-Globin Gene with a 4-Bp Promoter Deletion and Diminished AγT Expressiona,b,

Several factors influence the severity of homozygous β-thalassemia: β-thalassemia intermedia (non-transfusion dependent) patients often have at least one β + -thalassemia allele with only moderate impairment of β-globin production. β-thalassemia is also ameliorated by coinheritance of α-thalassemia or by γ-globin promoter mutations, such as T at position -158, which increase fetal hemoglobin production. In Sardinia, the codon 39 nonsense mutation (β39) is the primary cause of Β 0 -thalassemia. Two-thirds of northern Sardinian patients have this mutation on haplotype II, while one-fourth have it on haplotype I. Haplotype II, with ++ at the Hin d III sites in the G γ and A γ genes, is strongly associated with the variant A γ T globin, while haplotype I is associated with the normal A γ I . We have previously demonstrated that a β 0 -thalassemia haplotype found in a black family, with ++ at the Hin d III sites, had a 4-base-pair (bp) deletion at positions -225 to -222 of the A γ gene, in association with reduced A γ (elevated S γ ) levels. We have now extended this study to northern Sardinia, providing statistical data for the association of the 4-bp deletion with decreased A γ T expression.