β Thalassemia: studies of the molecular defect in the 'D' family

There are at least six postulated β Thalassemic gene defects. These include (1) reduced transcription as a result of altered binding of RNA polymerase, (2) reduced excision of RNA from the precursor protein (heteronuclear RNA), (3) reduced 5' capping, (4) reduced polyadenylation addition, (5) reduced translation, and (6) nonsense mutation leading to premature termination. Study of the propositus, M.D., of the 'D' family showed a low β/d synthesis ratio (0.24) despite a clinically mild disease. Polypeptide assembly of β chains was as rapid as normals, and quantitation of β mRNA was 0.70 that of α mRNA, a value that is surprisingly high for the degree of β chain synthesis deficiency. Both parents had β thal trait. It is postulated from this data that M.D. had two different thalassemic genes. The first is β° Catania, in which normal amounts of untranslatable β mRNA are present. This could be associated with a nonsense mutation leading to premature termination of β chain synthesis or with defective capping of the 5' end of the β mRNA, (see 3 and 6 above). The second is a β +thal gene, which in heterozygotes usually results in decreased amounts of β mRNA to the degree observed here.