title: Arg452 substitution of the erythroid-specific 5-aminolaevulinate synthase, a hot spot mutation in X-linked sideroblastic anaemia, does not itself affect enzyme activity.
abstract: Mutations of the erythroid-specific 5-aminolaevulinate synthase (ALAS2) gene are known to be responsible for X-linked sideroblastic anaemia (XLSA). An amino acid (AA) substitution for arginine at the 452 AA position of the ALAS2 protein is the most frequent mutation, which has been found in approximately one-quarter of patients with XLSA. Despite its high frequency, there has been no report on the enzymatic activity of Arg452 mutant proteins. In this study, we examined enzymatic activity in vitro of two Arg452 mutants, Arg452Cys and Arg452His, which were found in two new pedigrees of XLSA. While these mutations must be responsible for the clinical phenotype of XLSA in patients, the enzymatic activity and stability of these mutant proteins studied in vitro are indistinguishable from those of the wild type protein. These findings suggest that the Arg452 mutation of the ALAS2 gene by itself does not decrease the enzymatic activity or the stability in vitro, and that there may be an additional factor(s) in the bone marrow, which ensures the full ALAS2 activity in vivo.
authors.affiliation: Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Miyagi-ken, Japan. k-furuya@mail.tains.tohoku.ac.jp
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Furuyama
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
authors.forename: Tom
authors.initials: T
authors.lastname: Heller
authors.forename: Ben C J
authors.initials: BC
authors.lastname: Hamel
authors.forename: Elisabeth I
authors.initials: EI
authors.lastname: Minder
authors.forename: Toru
authors.initials: T
authors.lastname: Shimizu
authors.forename: Tadao
authors.initials: T
authors.lastname: Kuribara
authors.forename: Nicole
authors.initials: N
authors.lastname: Blijlevens
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shibahara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Sassa
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics* / Q000378:metabolism; D019943:Amino Acid Substitution; D000756:Anemia, Sideroblastic / Q000201:enzymology* / Q000235:genetics; D001120:Arginine / Q000235:genetics; D001853:Bone Marrow / Q000201:enzymology; D004912:Erythrocytes / Q000201:enzymology*; D040181:Genetic Diseases, X-Linked / Q000201:enzymology* / Q000235:genetics; D008040:Genetic Linkage; D009928:Organ Specificity / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation
chemical_list: D001120:Arginine; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human