title: Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone.
abstract: Fabry disease is an X-linked recessive inborn metabolic disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (EC 3.2.1.22). The causative mutations are diverse, include both large rearrangements and single-base substitutions, and are dispersed throughout the 7 exons of the alpha-galactosidase A gene (GLA). Mutation hotspots for Fabry disease do not exist. We examined 62 Fabry patients in Japan and found 24 GLA mutations, including 11 novel ones. A potential treatment reported for Fabry disease is active site specific chaperone (ASSC) therapy using 1-deoxygalactonojirimycin (DGJ), an inhibitor of alpha-galactosidase A, at subinhibitory concentrations. We transfected COS-7 cells with the 24 mutant GLAs and analyzed the alpha-galactosidase A activities. We then treated the transfected COS-7 cells with DGJ and analyzed its effect on the mutant enzyme activities. The activity of 11 missense mutants increased significantly with DGJ. Although ASSC therapy is useful only for misfolding mutants and therefore not applicable to all cases, it may be useful for treating many Japanese patients with Fabry disease.
authors.affiliation: Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shimotori
authors.forename: Hiroki
authors.initials: H
authors.lastname: Maruyama
authors.forename: Gen
authors.initials: G
authors.lastname: Nakamura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Suyama
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sakamoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Itoh
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Miyabayashi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ohnishi
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
authors.forename: Mari
authors.initials: M
authors.lastname: Wataya-Kaneda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kubota
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Mori
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tamura
authors.forename: Shinji
authors.initials: S
authors.lastname: Kageyama
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shio
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Maeba
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Yahagi
authors.forename: Motoko
authors.initials: M
authors.lastname: Tanaka
authors.forename: Masayo
authors.initials: M
authors.lastname: Oka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sugawara
authors.forename: Noriko
authors.initials: N
authors.lastname: Mori
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tamagaki
authors.forename: Shuuji
authors.initials: S
authors.lastname: Tanda
authors.forename: Yuka
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Chiya
authors.initials: C
authors.lastname: Shinonaga
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D044466:Asian People / Q000235:genetics*; D001665:Binding Sites; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D000795:Fabry Disease / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007564:Japan; D008875:Middle Aged; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D018832:Molecular Chaperones; D000519:alpha-Galactosidase