Murine mucopolysaccharidosis type I: Targeted disruption of the murine alpha-L-iduronidase gene
Murine mucopolysaccharidosis type I: Targeted disruption of the murine alpha-L-iduronidase gene
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DOI：
10.1093/hmg/6.4.503
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发表时间：
1997-04-01
影响因子：
3.5
通讯作者：
Jirik, FR
中科院分区：
文献类型：
--
作者：
Clarke, LA;Russell, CS;Jirik, FR
I型粘多糖沉积症（MPS I）被认为是典型的粘多糖沉积症的代表，尽管在MPS I亚组中观察到一系列严重程度，但Hurler综合征代表了MPS I最严重和最常见的表现。我们在此描述了通过靶向破坏鼠Idua基因来产生Hurler综合征的鼠模型，纯合子Idua -/-小鼠没有可检测到的α-L-艾杜糖醛酸酶活性，并且显示尿糖胺聚糖水平增加。尽管在出生时表现正常，但Idua -/-小鼠在3周龄时发展出扁平的面部轮廓和可辨别的手指增厚，在出生后的前20周内，没有观察到明显的生长缺陷或死亡率，X光片显示肋骨前部张开，早在4周龄时面部骨骼增厚，到15周龄时可检测到更广泛的骨发育不全，在4周龄时，主要在网状内皮细胞中注意到溶酶体储存，在枯否细胞、脾窦衬里细胞和神经胶质细胞中注意到丰富的溶酶体。到8周龄时，在肝细胞、软骨细胞、神经元因此，鼠Idua基因座的靶向破坏产生了代表MPS I严重形式的鼠品系。该模型应允许详细评价溶酶体贮积症的病理生理学，并为酶替代和基因治疗方案的测试和开发提供小动物模型。
Mucopolysaccharidosis type I (MPS I) is considered to represent the prototypical mucopolysaccharide storage disorder, Although a spectrum of severity is seen within the MPS I subgroup, Hurler syndrome represents the most severe and frequent manifestation of MPS I, We describe here the generation of a murine model for Hurler syndrome by targeted disruption of the murine Idua gene, Homozygous Idua -/- mice have no detectable alpha-L-iduronidase enzyme activity and show increased urinary glycosaminoglycan levels, Although normal appearing at birth, Idua -/- mice develop a flattened facial profile and thickening of the digits discernible by 3 weeks of age, No obvious growth deficiency nor mortality is seen within the first 20 weeks of life, Radiographs reveal anterior flaring of the ribs and thickening of the facial bones as early as 4 weeks of age with more extensive dysostosis detectable by 15 weeks of age, At 4 weeks of age, lysosomal storage is noted primarily within reticuloendothelial cells with abundant lysosomes noted in Kupffer cells, splenic sinusoidal lining cells, and glial cells, More widespread lysosomal storage is noted by 8 weeks of age in hepatocytes, chondrocytes, neurons, as well as renal tubular cells, Thus, targeted disruption of the murine Idua locus has produced a murine strain representative of the severe form of MPS I, This model should permit detailed evaluation of the pathophysiology of lysosomal storage disorders and provide a small animal model for the testing and development of enzyme replacement and gene therapy regimes.