MOLECULAR GENETICS OF IDURONATE SULFATASE DEFICIENCIES

在两个病例中发现了溶酶体酶艾杜酸硫酸酯酶缺陷 遗传性疾病、亨特综合征和多发性硫酸酯酶缺乏症。 亨特综合征，是一种遗传的X连锁隐性疾病，是 由于艾杜酸硫酸酯酶的缺乏。猎人的两种形态 综合征，轻度和重度，几乎完全缺乏艾杜酸 硫酸盐酶活性，不能用生化方法区分。不是 大多数患者都有明确的治疗方法 粘多糖病(MPS)，尽管这些疾病是潜在的 基因治疗的候选人。艾杜酸硫酸酯酶也是已知的 多发性硫酸酯酶缺乏症与至少六种其他疾病一起减少 硫酸盐酶。这种疾病结合了MPS和异色性的特征 脑白质营养不良。 这项建议的主要目标是确定基因的性质 轻、重度Hunter综合征和多发性骨髓瘤患者的缺陷 蛋白质和分子水平上的硫酸酶缺乏症。生物合成 放射性标记突变艾杜酸硫酸酯酶蛋白的研究将在 免疫沉淀和聚丙烯酰胺凝胶在成纤维细胞中的应用 电泳法。人艾杜糖酸盐基因的分子克隆 硫酸盐酶将利用两种可能的方法之一。Gt11人类 胎盘c DNA表达文库将用抗体或AN进行筛选 寡核苷酸探针将从氨基酸序列数据中构建。 分离的cDNA克隆将用于鉴定Hunter缺陷 综合征和多发性硫酸酶缺乏症在基因组和mRNA水平上。 这些结果应该会提高我们对临床的认识。 艾杜酸硫酸酯酶患者体内观察到的异质性 缺乏症。的限制性片段长度多态研究 艾杜酸硫酸酯酶基因座应能改进携带者检测 亨特综合征。艾杜糖酸酯的分子遗传学研究进展 硫酸酯酶缺陷将成为未来基因转移研究的基础 亨特综合症。

A deficiency of the lysosomal enzyme iduronate sulfatase is found in two genetic diseases, Hunter syndrome and multiple sulfatase deficiency. Hunter syndrome, which is inherited as an X-linked recessive disorder, is due to the deficiency of iduronate sulfatase. The two forms of Hunter syndrome, mild and severe, have nearly total deficiency of iduronate sulfatase activity and cannot be distinguished biochemically. No definitive treatment is available for most patients with mucopolysaccharidoses (MPS), although these disorders are potential candidates for gene therapy. Iduronate sulfatase is also known to be decreased in multiple sulfatase deficiency along with at least six other sulfatases. This disorder combines features of MPS and metachromatic leukodystrophy. The major goals of this proposal are to determine the nature of the genetic defects in patients with mild and severe Hunter syndrome and multiple sulfatase deficiency at the protein and molecular levels. The biosynthesis of the radiolabeled mutant iduronate sulfatase proteins will be studied in fibroblasts using immunoprecipitation and polyacrylamide gel electrophoresis. The molecular cloning of a cDNA for human iduronate sulfatase will utilize one of two possible approaches. A gt11 human placenta cDNA expression library will be screened with antibody or an oligonucleotide probe will be constructed from amino acid sequence data. The isolated cDNA clone will be used to characterize the defects in Hunter syndrome and multiple sulfatase deficiency at the genomic and mRNA levels. These results should enhance our understanding of the clinical heterogeneity observed in the patients with iduronate sulfatase deficiency. Restriction fragment length polymorphism studies at the iduronate sulfatase gene locus should allow improved carrier detection in Hunter syndrome. The studies on the molecular genetics of iduronate sulfatase deficiencies will form the basis for future gene transfer studies in Hunter syndrome.