Studies on the Mechanism of Abnormal Proteolysis in Erythrocytes of Thalassemic Patients and its Application to Clinical Diagnosis

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According to our original plan, we, Japanese and Thai, studies the mechanisms of abnormal proteolysis in the red blood cell of thalassemic patients, by exchanging material and information. Our analysis at clinical and molecular levels indicated that phenotypic manifestation of the disease is influenced not only by mutated genotypes but also by other factors ; the red cells of beta-thallasemia/Hb E patients with similar genetic defects were not always similar but variable in the hemoglobin content. We tentatively identified the following three factors that may modify clinical manifestation of thalassemia ; an interaction between alpha- and beta-thalassemia genes or their products, a structure or function of HbF gene, and Hb F gene, and protease activities. The first factor was suggested by the finding of amiliolated severity of beta-thalassemic patients with alpha-thalassemia gene. The second factor was indicated by the finding that homozygotes (+/+) with regard to XmuI restriction site (158 mucleotides upstream from the ^Ggamma gene) in the beta-globin gene cluster had significantly higher levels of hemoglobin than heterozygoted (+/-) of homozygotes (-/-). The last factor was suggested by a higher activity of calpain (Ca^<2+>-dependent cysteine protease), though accompanied by a higher activity of calpastatin (an endogenous inhibitor of calpain), in thalassemic red cells than in normal cells. Partial degradation of membrane proteins was also detected in thalassemic red cells. These results indicate the importance of the ratio of alpha- and beta-type globins as well as the activity of proteases in clinical investigation of thalassemia.