MOLECULAR-GENETICS OF MUCOPOLYSACCHARIDOSIS TYPE .1. DIAGNOSTIC, CLINICAL, AND BIOLOGICAL IMPLICATIONS
MOLECULAR-GENETICS OF MUCOPOLYSACCHARIDOSIS TYPE .1. DIAGNOSTIC, CLINICAL, AND BIOLOGICAL IMPLICATIONS
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DOI：
10.1002/humu.1380060403
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发表时间：
1995-01-01
期刊：
影响因子：
3.9
通讯作者：
HOPWOOD, JJ
中科院分区：
文献类型：
--
作者：
SCOTT, HS;BUNGE, S;HOPWOOD, JJ
I型粘多糖样变性（MPS-I）是一种由α-L-艾杜糖醛酸酶（IDUA）基因突变引起的常染色体隐性遗传疾病。这些突变导致糖苷酶α-L-艾杜糖醛酸酶（IDUA）缺乏，这是硫酸乙酰肝素和硫酸皮肤素降解所必需的，因此这些糖胺聚糖在溶酶体中储存。在MPS-I中有广泛的临床表型（命名：Hurler综合征，重度; Hurler/Scheie综合征，中度; Scheie综合征，轻度），这使得疾病严重程度的预测和遗传咨询变得困难。然而，自从IDUA基因克隆以来，突变分析为MPS-I表型的范围提供了一些分子解释，从而促进了接受实验性治疗方案（如骨髓移植）的患者的选择和评估。目前已确定MPS-I共有46个突变，包括8个无义突变、21个错义突变、3个剪接位点突变和14个微小缺失和/或插入。此外，30个多态性或非致病性序列变异已被确定，包括7个氨基酸取代。在欧洲血统的患者中，有两个主要的MPS-I突变和一些不太常见的突变。有可能对292名患者进行突变分析，这些患者可以分为8个不同种族和/或地理来源的主要患者组，突变等位基因频率存在显著差异。一个复杂的分子异质性正在出现，建立一个有价值的数据库基因型/表型相关性。突变分析也为IDUA的结构和功能提供了一些初步线索。(C)1995 Wiley-Liss，Inc.
Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive disease caused by mutations in the alpha-L-iduronidase (IDUA) gene. These mutations lead to a deficiency of the glycosidase alpha-L-iduronidase (IDUA), which is required for the degradation of heparan sulphate and dermatan sulphate and thus the storage of these glycosaminoglycans in the lysosome. There is a wide range of clinical phenotypes in MPS-I (eponyms: Hurler syndrome, severe; Hurler/Scheie syndrome, intermediate; Scheie syndrome, mild), which makes prediction of disease severity and genetic counselling difficult. However, since cloning of the IDUA gene, mutation analysis has provided some molecular explanations for the range of MPS-I phenotypes, in turn facilitating the selection and evaluation of patients undergoing experimental treatment protocols such as bone marrow transplantation. A total of 46 mutations now have been defined for MPS-I consisting of 8 nonsense mutations, 21 missense mutations, 3 splice site mutations, and 14 minor deletions and/or insertions. Furthermore, 30 polymorphisms or nonpathogenic sequence variants have been defined, including 7 amino acid substitutions. Among patients of European origin, there are two major MPS-I mutations and a number of less frequent mutations. It is possible to follow mutation analysis of 292 patients, which can be divided into eight main patient groups of different ethnic and/or geographic origin with significant variation in mutant allele frequencies. A complex picture of molecular heterogeneity is emerging, building a valuable database for genotype/phenotype correlation. Mutation analysis is also providing some of the first clues into the structure and function of IDUA. (C) 1995 Wiley-Liss, Inc.