MOLECULAR GENETIC STUDIES OF THE MUCOPOLYSACCHARIDOSES

在特定遗传疾病中发现的表型异质性提供了 有机会检查导致所观察到的 临床多样性。粘多糖病IH、IH/S或ALL患者 α-L-艾杜糖醛酸酶缺乏，但酶活性异常 仅靠活动不足以解释严重程度的巨大差异。 这种疾病的三个主要变种的症状。一如既往 对于其他溶酶体疾病，很可能有一种描述 突变对细胞内生物合成的影响 α-L-艾杜糖醛酸酶的区划和降解将带来启示 关于转录、翻译或其他蛋白质的意义 导致神经性和非神经性的处理异常 这些疾病的特征。这些研究的目的是定义 这组粘多糖病的异常生化和TO 描述导致以下症状变化的因素 分子方面的患者。为了实现这一目标，α-L-艾杜糖酸酶 是从人胎盘中提纯的。这使得对两个人的研究 该酶的生化和免疫学性质。脉搏追逐和 用正常和突变细胞系对α-艾杜糖醛酸酶的Western分析 用来阐明可能被证明是 具有个体表型特征的。关于处理的研究 分离基因的工作正在进行中。全长cDNA克隆的分离 编码正常人类α-L-艾杜糖醛酸酶允许更详细地研究 染色体基因座、基因变异及其控制因素 基因的表达。这些研究允许制定治疗性的 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.