MOLECULAR DEFECTS OF ERYTHROID 5-AMINOLEVULINATE SYNTHASE IN X-LINKEDSIDEROBLASTIC ANEMIA

The erythroid-specific isozyme of 5-aminolevulinate synthase (ALAS2), the first and rate-limiting enzyme of heme biosynthesis, is expressed concomitantly with the differentiation and maturation of the erythroid cell in order to accommodate generation of the large amounts of heme required for hemoglobin production. During the past few years the ALAS 2 gene and its transcript have been characterized and the amino acid s equence of the enzyme deduced. The human genetic disorder X-linked sid eroblastic anemia, previously postulated to be caused by defects of AL AS, has now been analyzed at the molecular and tissue-specific level. A heterogeneous group of point mutations in the catalytic domain of th e ALAS2 enzyme has been found to cause the disorder. Impaired activity of recombinant mutant ALAS2 enzymes has also been demonstrated. Chara cterization of molecular defects in individuals with X-linked siderobl astic anemia has provided improved diagnosis for at-risk family member s.