Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone
Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone
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DOI：
10.1002/humu.9520
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发表时间：
2008-02-01
期刊：
影响因子：
3.9
通讯作者：
Gejyo, Fumitake
中科院分区：
文献类型：
--
作者：
Shimotori, Masaaki;Maruyama, Hiroki;Gejyo, Fumitake
法布里病是一种X连锁隐性遗传的先天性代谢紊乱，由溶酶体酶α-半乳糖苷酶A缺乏引起（EC 3.2.1.22）。致病突变是多样的，包括大的重排和单碱基取代，并且分散在α-半乳糖苷酶A基因（GLA）的7个外显子中。法布里病的突变热点不存在。我们检查了日本62例法布里病患者，发现24个GLA突变，包括11个新的。报道的法布里病的潜在治疗是使用亚抑制浓度的α-半乳糖苷酶A抑制剂1-脱氧半乳糖野尻霉素（DGJ）的活性位点特异性伴侣（ASSC）治疗。我们用24个突变GLAs转染COS-7细胞，并分析α-半乳糖苷酶A的活性。然后用DGJ处理转染的COS-7细胞，分析其对突变酶活性的影响。11个错义突变体的酶活性在DGJ作用下显著提高。虽然ASSC疗法仅适用于错误折叠突变体，因此不适用于所有病例，但它可能适用于治疗许多日本法布里病患者。(C)2007 Wiley-Liss，Inc.
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. (C) 2007 Wiley-Liss, Inc.