MOLECULAR GENETICS OF IDURONATE SULFATASE DEFICIENCIES

在两例患者中发现了溶酶体酶艾杜糖醛酸硫酸酯酶的缺乏， 遗传性疾病、亨特氏综合征和多发性硫酸酯酶缺乏症。 亨特氏综合征是一种X连锁隐性遗传疾病， 这是由于艾杜糖醛酸硫酸酯酶缺乏所致。 猎人的两种形式 轻度和重度综合征几乎完全缺乏艾杜糖醛酸 硫酸酯酶活性，并且不能在生物化学上区分。 没有 对于大多数患有以下疾病的患者， 粘多糖沉积症（MPS），尽管这些疾病是潜在的 基因治疗的候选人 艾杜糖醛酸硫酸酯酶也已知是 减少多发性硫酸酯酶缺乏症沿着至少六个其他 硫酸酯酶 这种疾病结合了MPS和异染性的特征 脑白质营养不良 这项建议的主要目标是确定遗传的性质， 轻度和重度亨特氏综合征和多个 蛋白质和分子水平的硫酸酯酶缺乏。 生物合成 将研究放射性标记的突变艾杜糖酸硫酸酯酶蛋白 用免疫沉淀和聚丙烯酰胺凝胶 电泳 人艾杜糖醛酸cDNA的分子克隆 硫酸酯酶将利用两种可能方法之一。 一个gt11人类 胎盘cDNA表达文库将用抗体或 寡核苷酸探针将从氨基酸序列数据构建。 分离的cDNA克隆将用于表征Hunter中的缺陷。 综合征和多发性硫酸酯酶缺乏症的基因组和mRNA水平。 这些结果应该加强我们对临床的理解。 在艾杜糖醛酸硫酸酯酶患者中观察到的异质性 缺陷 限制性片段长度多态性研究 艾杜糖醛酸硫酸酯酶基因座应允许改善的携带者检测， 亨特氏综合症。 艾杜糖醛酸酯的分子遗传学研究 硫酸酯酶缺陷将成为未来基因转移研究的基础 亨特氏综合症

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.