Shimotori Masaaki, Maruyama Hiroki, Nakamura Gen, Suyama Takayuki, Sakamoto Fumiko, Itoh Masaaki, Miyabayashi Shigeaki, Ohnishi Takahiro, Sakai Norio, Wataya-Kaneda 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, Shinonaga Chiya, Miyazaki Jun-ichi, Ishii Satoshi, Gejyo Fumitake
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Hum Mutat. 2008 Feb;29(2):331. doi: 10.1002/humu.9520.
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.
法布里病是一种X连锁隐性先天性代谢紊乱疾病，由溶酶体酶α-半乳糖苷酶A（EC 3.2.1.22）缺乏引起。致病突变多种多样，包括大片段重排和单碱基替换，且分布于α-半乳糖苷酶A基因（GLA）的7个外显子中。法布里病不存在突变热点。我们对日本的62名法布里病患者进行了检测，发现了24种GLA突变，其中包括11种新突变。据报道，法布里病的一种潜在治疗方法是使用α-半乳糖苷酶A抑制剂1-脱氧半乳糖野茉莉霉素（DGJ）在亚抑制浓度下进行活性位点特异性伴侣（ASSC）治疗。我们用24种突变型GLA转染COS-7细胞，并分析α-半乳糖苷酶A的活性。然后我们用DGJ处理转染后的COS-7细胞，并分析其对突变酶活性的影响。11种错义突变体的活性在DGJ作用下显著增加。虽然ASSC治疗仅对错误折叠的突变体有用，因此不适用于所有病例，但它可能对治疗许多日本法布里病患者有用。
