title: Pyridoxine refractory X-linked sideroblastic anemia caused by a point mutation in the erythroid 5-aminolevulinate synthase gene.
abstract: To elucidate how pyridoxine-refractory X-linked sideroblastic anemia (XLSA) develops, we analyzed the erythroid-specific 5-aminolevulinate synthase (ALAS-E) gene of a patient with the anemia. The activity and amount of the enzyme in bone marrow cells of the patient were found to be approximately 5% of the normal control. We identified a point mutation, which introduces an amino acid substitution from Asp 190 to Val. In transient transfection analyses using quail fibroblasts, accumulation of aberrantly processed proteins, the sizes of which were larger than that of mature ALAS-E, was found in mitochondria. The proteins were reproducibly detected in assays combining in vitro transcription/translation of ALAS-E precursor and import of the precursor into isolated mouse mitochondria. These results suggest that the mutation causing pyridoxine-refractory XLSA affects the processing of the ALAS-E precursor, thus provoking instability of the ALAS-E protein.
authors.affiliation: Department of Biochemistry, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Furuyama
authors.forename: H
authors.initials: H
authors.lastname: Fujita
authors.forename: T
authors.initials: T
authors.lastname: Nagai
authors.forename: K
authors.initials: K
authors.lastname: Yomogida
authors.forename: H
authors.initials: H
authors.lastname: Munakata
authors.forename: M
authors.initials: M
authors.lastname: Kondo
authors.forename: A
authors.initials: A
authors.lastname: Kimura
authors.forename: A
authors.initials: A
authors.lastname: Kuramoto
authors.forename: N
authors.initials: N
authors.lastname: Hayashi
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D000756:Anemia, Sideroblastic / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D001224:Aspartic Acid; D001483:Base Sequence; D001853:Bone Marrow / Q000201:enzymology; D017931:DNA Primers; D005091:Exons; D005260:Female; D015723:Gene Library; D006801:Humans; D007438:Introns; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D017354:Point Mutation; D014176:Protein Biosynthesis; D011736:Pyridoxine / Q000627:therapeutic use*; D051381:Rats; D015203:Reproducibility of Results; D014158:Transcription, Genetic; D014633:Valine; D014960:X Chromosome
chemical_list: D017931:DNA Primers; D001224:Aspartic Acid; D000624:5-Aminolevulinate Synthetase; D014633:Valine; D011736:Pyridoxine