Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone.
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.
Shimotori
Masaaki
M
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Maruyama
Hiroki
H
Nakamura
Gen
G
Suyama
Takayuki
T
Sakamoto
Fumiko
F
Itoh
Masaaki
M
Miyabayashi
Shigeaki
S
Ohnishi
Takahiro
T
Sakai
Norio
N
Wataya-Kaneda
Mari
M
Kubota
Mitsuru
M
Takahashi
Toshiyuki
T
Mori
Tatsuhiko
T
Tamura
Katsuhiko
K
Kageyama
Shinji
S
Shio
Nobuo
N
Maeba
Teruhiko
T
Yahagi
Hirokazu
H
Tanaka
Motoko
M
Oka
Masayo
M
Sugiyama
Hitoshi
H
Sugawara
Toshiyuki
T
Mori
Noriko
N
Tsukamoto
Hiroko
H
Tamagaki
Keiichi
K
Tanda
Shuuji
S
Suzuki
Yuka
Y
Shinonaga
Chiya
C
Miyazaki
Jun-ichi
J
Ishii
Satoshi
S
Gejyo
Fumitake
F
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*
D018832:Molecular Chaperones; D000519:alpha-Galactosidase