Matsuzawa Fumiko, Aikawa Sei-ichi, Doi Hirofumi, Okumiya Toshika, Sakuraba Hitoshi
Celestar Lexico-Sciences Inc., MTG-17, 1-3 Nakase, Chiba 261-8501, Japan.
Hum Genet. 2005 Aug;117(4):317-28. doi: 10.1007/s00439-005-1300-5. Epub 2005 May 28.
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.
法布里病包括典型和变异型表型。前者需要早期酶替代疗法，而半乳糖输注对一些变异型病例有效。在不久的将来将开始尝试在症状出现前进行早期诊断。然而，仅从基因信息很难预测表型、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。我们构建了由161个错义突变（147个典型突变和14个变异突变）产生的突变α-半乳糖苷酶的结构模型，并通过计算受影响原子的数量来评估每个置换对结构的影响。其中，对11个已进行生化特征分析的突变体，通过对受影响原子的彩色成像进行了进一步研究。在变异型组中，氨基酸置换影响的原子数量较少，尤其是在主链中。在85%的病例中，主链中受影响的原子少于三个。在该组中，位于远离活性位点的小结构变化导致突变酶不稳定，但半乳糖可以使其稳定。典型法布里突变引起的结构变化通常较大或位于功能重要区域。在82%的病例中，主链中有三个或更多原子受到影响。典型组包括功能失调和不稳定类型，半乳糖预计无法稳定突变酶。本研究证明了结构变化与临床和生化表型之间的相关性。结构研究有助于阐明法布里病的发病基础和临床治疗。
