Animal models for X-linked sideroblastic anemia.

Erythroid 5-aminolevulinate synthase (ALAS-E) catalyzes the first step of heme biosynthesis in erythroid cells. Several lines of evidence suggest that the expression of ALAS-E is important for the process of erythroid differentiation, which requires a large amount of heme for hemoglobin production. Mutation of human ALAS-E causes the disorder X-linked sideroblastic anemia (XLSA). More than 25 unrelated ALAS-E mutations in XLSA patients have been reported. Most XLSA cases are of the pyridoxine-responsive type, but molecular diagnosis of 1 pyridoxine-refractory type XLSA has also been reported. To examine the roles heme plays during hematopoiesis and to create animal models of XLSA, we disrupted the mouse ALAS-E gene. A chemically induced zebrafish mutant (sau) that lacks ALAS-E has also been isolated. Analysis of these ALAS-E mutants unequivocally demonstrated that ALAS-E is the principal isozyme contributing to erythroid heme biosynthesis In ALAS-E-null mutant mouse embryos, erythroid differentiation was arrested, and an abnormal hematopoietic cell fraction emerged that accumulated a large amount of iron diffusely in the cytoplasm. This accumulation of iron was in contrast to that in XLSA patients, as typical ring sideroblasts accumulated iron primarily in mitochondria. These observations suggest that the mode of iron accumulation caused by the lack of ALAS-E is different in primitive and definitive erythroid cells. Thus ALAS-E, and hence heme supply, is necessary for erythroid cell differentiation and iron metabolism.