Premium
Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone
Author(s) -
Shimotori Masaaki,
Maruyama Hiroki,
Nakamura Gen,
Suyama Takayuki,
Sakamoto Fumiko,
Itoh Masaaki,
Miyabayashi Shigeaki,
Ohnishi Takahiro,
Sakai Norio,
WatayaKaneda Mari,
Kubota Mitsuru,
Takahashi Toshiyuki,
Mori Tatsuhiko,
Tamura Katsuhiko,
Kageyama Shinji,
Shio Nobuo,
Maeba Teruhiko,
Yahagi Hirokazu,
Tanaka Motoko,
Oka Masayo,
Sugiyama Hitoshi,
Sugawara Toshiyuki,
Mori Noriko,
Tsukamoto Hiroko,
Tamagaki Keiichi,
Tanda Shuuji,
Suzuki Yuka,
Shiaga Chiya,
Miyazaki Junichi,
Ishii Satoshi,
Gejyo Fumitake
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9520
Subject(s) - fabry disease , biology , mutant , missense mutation , transfection , gene , exon , alpha galactosidase , mutation , microbiology and biotechnology , genetics , disease , pathology , medicine
Fabry disease is an X‐linked recessive inborn metabolic disorder caused by a deficiency of the lysosomal enzyme α‐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 α‐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 α‐galactosidase A, at subinhibitory concentrations. We transfected COS‐7 cells with the 24 mutant GLA s and analyzed the α‐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. © 2007 Wiley‐Liss, Inc.