MOLECULAR GENETIC STUDIES OF THE MUCOPOLYSACCHARIDOSES

在特定遗传疾病中观察到的表型异质性提供了 有机会检查负责观察到的突变事件 临床多样性 粘多糖沉积症IH、IH/S或IS患者 缺乏α-L-艾杜糖醛酸酶，但酶的异常 活动本身不足以解释严重程度的巨大差异 三种主要变异的症状。 如已经 对于其他溶酶体疾病，很可能是一个描述 突变对生物合成的影响，细胞内 α-L-艾杜糖醛酸酶的区室化和降解将揭示 转录、翻译或其他蛋白质的重要性 处理异常，导致神经和非神经 这些疾病的特点。 这些研究的目的是确定 这组粘多糖沉积症的异常生物化学， 描述导致症状变化的因素， 患者在分子水平上 为了实现这一目标，α-L-艾杜糖醛酸酶 是从人胎盘中提纯的 这使得研究 这种酶的生物化学和免疫学特性。 脉冲追踪和 使用正常和突变细胞系的α-艾杜糖醛酸酶的Western分析 以阐明蛋白质多态性， 个体表型的特征。 研究涉及 基因的分离正在进行中。 cDNA克隆的分离 编码正常人α-L-艾杜糖醛酸酶允许更详细地研究 染色体位点，基因变异，以及控制 基因的表达。 这些研究允许配制治疗药物 利用基因产物和重组DNA方法的策略。

Phenotypic heterogeneity seen within specific genetic disorders provides an opportunity to examine the mutational events responsible for the observed clinical diversity. Patients with mucopolysaccharidoses IH, IH/S or IS all have a deficiency of Alpha-L-iduronidase, but the abnormality of enzymatic activity alone is insufficient to explain the wide differences in severity of symptoms in the three major variants of the disorder. As has been demonstrated for other lysosomal disorders, it is likely that a description of the effect of mutations on the biosynthesis, intracellular compartmentalization and degradation of Alpha-L-iduronidase will shed light on the significance of transcriptional, translational or other protein processing abnormalities that result in the neurologic and non-neurologic features of these diseases. The aim of these studies is to define the abnormal biochemistry of this group of mucopolysaccharidoses and to characterize the factors responsible for variations in symptoms among patients in molecular terms. To achieve this goal, the Alpha-L-iduronidase was purified from human placenta. This has allowed the study of both the biochemical and immunological properties of this enzyme. Pulse-chase and western analyses of Alpha-iduronidase using normal and mutant cell lines were performed to elucidate protein polymorphisms that may prove to be characteristic of the individual phenotypes. Studies dealing with the isolation of the gene are in progress. The isolation of cDNA clones encoding normal human Alpha-L-iduronidase permit a more detailed study of the chromosomal locus, gene variants, as well as the factors controlling expression of the gene. These studies allow formulation of therapeutic strategies utilizing both gene product and recombinant DNA approaches.