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Pyridoxine Refractory X-Linked Sideroblastic Anemia Caused by a Point Mutation in the Erythroid 5-Aminolevulinate Synthase Gene
Kazumichi Furuyama,
Hiroyoshi Fujita,
Tadashi Nagai,
Kentaro Yomogida,
Hiroshi Munakata,
Masao Kondo,
Akiro Kimura,
Atsushi Kuramoto,
Norio Hayashi, and
Masayuki Yamamoto
From the Departments of Biochemistry and Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai; The Institute of Public Health, Ministry of Health and Welfare, Tokyo; Departments of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima; Center for TARA and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
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.
Blood, Vol. 90 No. 2 (July 15), 1997:
pp. 822-830
© 1997 by The American Society of Hematology.
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