Kazumichi Furuyama

A novel mutation of the erythroid-specific delta-aminolaevulinate synthase gene in a patient with X-linked sideroblastic anaemia.

A novel missense mutation, A1754G, in exon 11 of the erythroid‐specific δ‐aminolaevulinate synthase gene (ALAS2) was identified in a Japanese male with sideroblastic anaemia. ALAS activity in bone marrow cells of the patient was reduced to 53.3% of the normal control. Consistent with this finding, activity of a bacterially expressed ALAS2 mutant protein harbouring this mutation was 19.5% compared with the normal control, but was increased up to 31.6% by the addition of pyridoxal 5′‐phosphate (PLP) in vitro. RFLP analysis with Bsp HI restriction revealed that his mother was a carrier of the mutation. These findings suggest that A1754G mutation was inherited in this family in a manner consistent with X‐linked inheritance, and is responsible for sideroblastic anaemia in the patient.

R411C mutation of the ALAS2 gene encodes a pyridoxine‐responsive enzyme with low activity

A R411C missense mutation of the erythroid‐specific δ‐aminolaevulinate synthase (ALAS2) gene was identified in a pedigree with X‐linked pyridoxine‐responsive sideroblastic anaemia (XLSA). The normal and the mutant cDNAs were expressed in E. coli, and the enzyme protein was purified. ALAS activity of the mutant enzyme was 12% and 25%, when incubated in the absence and the presence of pyridoxal 5′‐phosphate, respectively, compared with that of the wild‐type enzyme. These findings suggest that the R411C mutation accounts for low ALAS activity and a partial pyridoxine‐responsiveness of the disease in the patient.

A novel mutation of the erythroid‐specific δ‐aminolevulinate synthase gene in a patient with non‐inherited pyridoxine‐responsive sideroblastic anemia

A novel missense mutation, G663A, in exon 5 of the erythroid‐specific δ‐aminolevulinate synthase gene (ALAS2) was identified in a Japanese male with pyridoxine‐responsive sideroblastic anemia. Activity of the mutant δ‐aminolevulinate synthase protein expressed in vitro was 15.1% compared with the normal control, but was increased up to 34.5% by the addition of pyridoxal 5′‐phosphate, consistent with the clinical response of the patient to pyridoxine treatment. The same mutation was also detected in genomic DNA from the oral mucosal membrane of the patient; however, it was not detected in other family members. These findings suggest that this G663A mutation is responsible for sideroblastic anemia in the proband, and may be an index mutation in this pedigree. Am. J. Hematol. 62:112–114, 1999.