Molecular Basis for Nondeletion a - Thalassemia in American Blacks a 2116 GAG -

An American black woman was found to have the phenotype of moderately severe a-thalassemia normally associated with the loss of two to three a-globin genes despite an a-gl9bin gene map that demonstrated the loss of only a single a-globin gene (-a/ aa). Several individuals in her kindred with normal a-globin gene mapping studies (aa/aa) had mild a-thalassemia hematologic values consistent with the loss of one to two a-globin genes. These data suggested the presence of a nondeletion athalassemia defect in this family which segregates with the intact aa gene cluster. An abnormally migrating and highly unstable a-globin gene product was demonstrated by in vitro translation of the reticulocyte mRNA from the proposita and this mutant a-globin protein was mapped to the a2-globin gene by hybridselected translation. The abnormal a2-globin gene was cloned and sequenced. A single base mutation that results in a premature termination codon was identified at codon 116 (GAG -* UAG). The defined a-globin genotype of the proposita (-a/all6UAGa) and the positioning of this nonsense mutation at the a2-globin gene locus are fully consistent with the observed a-thalassemia