Sugawara Kanako, Ohno Kazuki, Saito Seiji, Sakuraba Hitoshi
Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
NPO for the Promotion of Research on Intellectual Property Tokyo, Tokyo, Japan.
J Hum Genet. 2008;53(9):812-824. doi: 10.1007/s10038-008-0316-9. Epub 2008 Jul 17.
Fabry disease is an inborn error of glycolipid catabolism resulting from lesions in the gene encoding alpha-galactosidase (GLA). To elucidate the basis of Fabry disease, we constructed structural models of mutant GLAs responsible for the disease and calculated indexes, i.e., the numbers of atoms affected in the main chain and side chain of each mutant GLA, the root-mean-square distance values, and the solvent-accessible surface-area values, based on 212 Fabry amino acid substitutions previously reported (196 classic and 16 variant). As two therapeutic options, enzyme replacement and enzyme enhancement, are now available for this disease, proper prediction of the natural outcome and therapeutic efficiency based on the molecular evidence for individual cases are critical for patients' quality of life. Our results revealed that structural changes in the classic Fabry group were generally large and tended to be in the core region of a protein or located in the functionally important region, including the active-site pocket. On the other hand, structural changes in the variant Fabry group were small or localized on the surface of the molecule far away from the active site. We focused on structural changes due to amino acid substitutions for which substrate analogues are effective for improving the stability or transportation of mutant GLAs, and the results of the study revealed that they are small or localized on the molecular surface, regardless of the phenotype. Coloring of affected atoms based on distances between wild type and mutant ones clearly showed the characteristic structural changes in the GLA protein geographically and subquantitatively. Structural investigation is useful for elucidation of the basis of Fabry disease and predicting disease outcome.
法布里病是一种糖脂分解代谢的先天性缺陷疾病，由编码α - 半乳糖苷酶（GLA）的基因突变引起。为了阐明法布里病的发病机制，我们构建了导致该疾病的突变型GLA的结构模型，并根据先前报道的212个法布里氨基酸替换（196个经典型和16个变异型）计算了各项指标，即每个突变型GLA主链和侧链中受影响的原子数、均方根距离值以及溶剂可及表面积值。由于目前针对该疾病有酶替代和酶增强两种治疗方案，基于个体病例的分子证据对自然转归和治疗效果进行准确预测对于患者的生活质量至关重要。我们的结果显示，经典型法布里组的结构变化通常较大，且倾向于发生在蛋白质的核心区域或功能重要区域，包括活性位点口袋。另一方面，变异型法布里组的结构变化较小或局限于远离活性位点的分子表面。我们关注了因氨基酸替换导致的结构变化，对于这些替换，底物类似物对改善突变型GLA的稳定性或转运有效，研究结果表明，无论表型如何，这些变化都较小或局限于分子表面。根据野生型和突变型之间的距离对受影响原子进行着色，清楚地从地理和定量角度展示了GLA蛋白的特征性结构变化。结构研究有助于阐明法布里病的发病机制并预测疾病转归。
