Sugawara Kanako, Saito Seiji, Ohno Kazuki, Okuyama Torayuki, Sakuraba Hitoshi
Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo, Japan.
J Hum Genet. 2008;53(5):467-474. doi: 10.1007/s10038-008-0272-4. Epub 2008 Mar 14.
To elucidate the basis of mucopolysaccharidosis type I (MPS I), we constructed structural models of mutant alpha-L: -iduronidases (IDUAs) resulting from 33 amino acid substitutions that lead to MPS I (17 severe, eight intermediate, and eight attenuated). Then, we examined the structural changes in the enzyme protein by calculating the number of atoms affected and determined the root-mean-square distance (RMSD) and the solvent-accessible surface area (ASA). In the severe MPS I group, the number of atoms influenced by a mutation and the average RMSD value were larger than those in the attenuated group, and the residues associated with the mutations identified in the severe group tended to be less solvent accessible than those in the attenuated group. The clinically intermediate phenotype group exhibited intermediate values for the numbers of atoms affected, RMSD, and ASA between those in the severe group and those in the attenuated group. The results indicated that large structural changes had occurred in the core region in the severe MPS I group and small ones on the molecular surface in the attenuated MPS I group. Color imaging revealed the distributions and degrees of the structural changes caused by representative mutations for MPS I. Thus, structural analysis is useful for elucidating the basis of MPS I. As there was a difference in IDUA structural change between the severe MPS I group and the attenuated one, except for a couple of mutations, structural analysis can help predict the clinical outcome of the disease.
为阐明I型黏多糖贮积症（MPS I）的发病机制，我们构建了由33种导致MPS I的氨基酸取代（17种严重型、8种中间型和8种轻型）所产生的突变α-L-艾杜糖醛酸酶（IDUAs）的结构模型。然后，我们通过计算受影响的原子数来研究酶蛋白的结构变化，并确定均方根距离（RMSD）和溶剂可及表面积（ASA）。在严重MPS I组中，受突变影响的原子数和平均RMSD值均大于轻型组，且严重组中与突变相关的残基的溶剂可及性往往低于轻型组。临床中间表型组在受影响的原子数、RMSD和ASA方面呈现出介于严重组和轻型组之间的中间值。结果表明，严重MPS I组的核心区域发生了较大的结构变化，而轻型MPS I组的分子表面发生了较小的结构变化。彩色成像揭示了由MPS I代表性突变引起的结构变化的分布和程度。因此，结构分析有助于阐明MPS I的发病机制。由于除少数突变外，严重MPS I组和轻型组的IDUA结构变化存在差异，结构分析有助于预测该疾病的临床结局。
