Fabry disease: correlation between structural changes in a-galactosidase, and clinical and biochemical phenotypes
Fabry disease: correlation between structural changes in a-galactosidase, and clinical and biochemical phenotypes
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DOI：
10.1007/s00439-005-1300-5
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发表时间：
2005-08-01
期刊：
影响因子：
5.3
通讯作者：
Sakuraba, H
中科院分区：
文献类型：
--
作者：
Matsuzawa, F;Aikawa, S;Sakuraba, H
法布里病包括经典表型和变异表型。前者需要早期酶替代治疗，半乳糖输注对某些变异病例有效。在症状出现之前进行早期诊断的尝试将在不久的将来开始。然而，仅从遗传信息很难预测其表型，确定治疗方法。因此，我们尝试从一个新的角度进行结构分析。我们建立了由161个错义突变（147个经典突变和14个变异突变）引起的α -半乳糖苷酶突变体的结构模型，并通过计算受影响的原子数来评估每次替换对结构的影响。其中11个突变体具有生物化学特征，并通过受影响原子的彩色成像进一步研究。在变异基团中，受氨基酸取代影响的原子数很少，特别是在主链中。在85%的情况下，主链中受影响的原子少于三个。在这一组中，位于活性位点之外的小结构变化导致突变酶的不稳定，但半乳糖可以稳定它们。由经典法布里突变引起的结构变化通常很大或位于功能重要的区域。在82%的情况下，主链上有三个或更多的原子受到影响。经典组包括功能失调和不稳定的类型，半乳糖不能稳定突变酶。该研究证明了结构变化与临床和生化表型的相关性。结构研究有助于阐明法布里病的发病基础和临床治疗。
Fabry disease comprises classic and variant phenotypes. The former needs early enzyme replacement therapy, and galactose infusion is effective for some variant cases. Attempts of early diagnosis before manifestations appear will begin in the near future. However, it is difficult to predict the phenotype, to determine the therapeutic approach, only from genetic information. Thus we attempted structural analysis from a novel viewpoint. We built structural models of mutant alpha-galactosidases resulting from 161 missense mutations (147 classic and 14 variant), and evaluated the influence of each replacement on the structure by calculating the numbers of atoms affected. Among them, 11 mutants, biochemically characterized, were further investigated by color imaging of the influenced atoms. In the variant group, the number of atoms influenced by amino-acid replacement was small, especially in the main chain. In 85% of the cases, less than three atoms in the main chain are influenced. In this group, small structural changes, located apart from the active site, result in destabilization of the mutant enzymes, but galactose can stabilize them. Structural changes caused by classic Fabry mutations are generally large or are located in functionally important regions. In 82% of the cases, three atoms or more in the main chain are affected. The classic group comprises dysfunctional and unstable types, and galactose is not expected to stabilize the mutant enzymes. This study demonstrated the correlation of structural changes, and clinical and biochemical phenotypes. Structural investigation is useful for elucidating the bases of Fabry disease and clinical treatment.