An a - Globin Gene Initiation Codon Mutation in a Black Family With HbH Disease

T HE HUMAN a-globin gene complex on chromosome 16 consists of two adult a-genes (al and ct2), an embryonic c-gene, and associated pseudogenes.’ Disorders of a-chain synthesis result in diminished (a thalassemia) or absent (a#{176}thalassemia) a-chain production from the affected chromosome. Molecular analysis has revealed ddetion and nondeletion defects of which, unlike the fl-thalassemias, deletion mutations are the most common.2 Four clinical syndromes of a-thalassemia are recognized: the silent carrier, characterized by the presence of three functional a-globin genes (aa/ -a); a-thalassemia trait, by the presence of two a-genes ( /aa) or ( a/ a); Hb H disease, by the presence of one a-gene (-/ -a); and hydrops fetalis in which no functional a-globin genes are present ( / )#{149}3 Varying extents of DNA deletions are responsible for these disorders. ’#{176} A less common class of a-thalassemia occurs in which the a-globin structural genes are grossly intact but contain mutations affecting RNA processing, RNA stability, and polyadenylation)322 Two mutations involving the initiation codon of the a-globin gene have been described. A dinucleotide deletion preceding the ATO initiation codon of an a-globin gene in an Algerian patient23’24 was responsible for a 30% to 50% reduction in translation efficiency of the aglobin RNA.22 A mutation within the initiation codon (ATG .-. ACG) of the a2 gene of a Sardinian patient abolished the function of this gene at the level of translation.25 In a single Sardinian individual, the NcoI restriction site in an a 1-globin gene was abolished by a mutation that was not characterized at the DNA sequence level but was presumed to be the same.26 We report here the first mutation within the initiation codon of an a-globin gene in a Black individual.