5-Aminolevulinate synthase in sideroblastic anemias: mRNA and enzyme activity levels in bone marrow cells

To examine the role of 5-aminolevulinate synthase (ALAS) in the pathogenesis of sideroblastic anemias, levels of mRNAs for erythroid and housekeeping ALAS isozymes were examined, and total ALAS activity was assessed in bone marrow cells. In two patients with X-linked sideroblastic anemia the levels of mRNA for erythroid ALAS as well as for alpha and beta globin appear to be decreased while levels of mRNA for glycophorin A in both patients were the same as in normal individuals. However, amounts of housekeeping ALAS mRNA were increased two- to threefold in these patients. Total ALAS activity was also increased two- or threefold, perhaps reflecting increased transcription of the housekeeping gene in response to diminished cellular heme in erythroid cells and/or enhanced translation of the erythroid isoform in response to iron accumulation. In a third patient with X-linked sideroblastic anemia ALAS activity was low but increased to twice the normal value after pyridoxine administration, suggesting a structural defect of the enzyme. In a fourth patient, with isolated congenital, pyridoxine-responsive sideroblastic anemia, the erythroid ALAS mRNA was normal and a low enzyme activity was strikingly enhanced by pyridoxal-phosphate albeit to subnormal levels. In idiopathic acquired sideroblastic anemia, ALAS mRNA for both isozymes was normal and enzyme activity was slightly elevated. These observations thus reflect heterogeneous aberrations of erythroid heme synthesis in the various types of sideroblastic anemia and suggest that defects involving erythroid ALAS underlie at least some of them.