beta zero thalassemia in Sardinia is caused by a nonsense mutation.

Abstract

A C T We report the characterization of a molecular lesion of (8 thalassemia in Sardinia. Beta thalassemia in this area is predominantly the (80 type with low levels of,8-globin mRNA. Translation assay of this messenger RNA in a cell-free system showed (- globin chain synthesis only with the addition of an amber (UAG) suppressor transfer RNA. Double- stranded complementary DNA prepared from recticu- locyte mRNA from a Sardinian patient was cloned in a bacterial plasmid and a,(3-globin complementary DNA containing clone was isolated and sequenced. At the position corresponding to amino acid number 39, a single nucleotide mutation converted a glutamine codon (CAG) to an amber termination codon (UAG). We previously reported an amber nonsense mutation at amino acid 17 as a cause of Chinese (80 thalassemia. Thus, i80 thalassemia in Sardinia represents the second example of a nonsense mutation, and we predict that other ,80 thalassemias with mutations at various points along the ,(-globin chain will be found to form a discrete subgroup of 10 thalassemia. These experiments further illustrate the heterogeneity of lesions that lead to defective globin chain synthesis in 8 thalassemia.