Decreased performance in IDUA knockout mouse mimic limitations of joint function and locomotion in patients with Hurler syndromeReport as inadecuate




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Orphanet Journal of Rare Diseases

, 10:121

Lysosomal storage diseases

Abstract

BackgroundMucopolysaccharidosis type I MPS I is caused by the deficiency of alpha-L-iduronidase IDUA, which is involved in the degradation of glycosaminoglycans GAGs, such as heparan sulfate and dermatan sulfate in the lysosome. It has been reported that joint symptoms are almost universal in MPS I patients, and even in the case of attenuated disease, they are the first symptom that brings a child to medical attention. However, functional tests and biological markers have not been published for the evaluation of the limitations in joint and locomotion in animal model-mimicking MPS.

MethodsWe generated IDUA knockout KO mice to observe whether they present impairment of joint function. KO mice were characterized phenotypically and tested dual-energy X-ray absorptiometry analysis DEXA, open-field, rotarod, and grip strength.

ResultsThe IDUA KO mice, generated by disruption between exon 6 and exon 9, exhibited clinical and laboratory findings, such as high urinary GAGs excretion, GAGs accumulation in various tissues, and significantly increased bone mineral density BMD in both female and male mice in the DEXA of the femur and whole bone. Remarkably, we observed a decrease in grasp function, decreased performance in the rotarod test, and hypo-activity in the open-field test, which mimic the limitations of joint mobility and decreased motor performance in the 6-min walk test in patients with MPS I.

ConclusionsWe generated a new IDUA KO mouse, tested open field, rotarod and grip strength and demonstrated decrease in grip strength, decreased performance and hypo-activity, which may be useful for investigating therapeutic approaches, and studying the pathogenesis of joint and locomotion symptoms in MPS I.

KeywordsIDUA IDUA KO mice BMD Rotarod test Open-field test AbbreviationsMPS IMucopolysaccharidosis type I

MPS I-HHurler syndrome

MPS I-SScheie syndorme

MPS I-HSHurler-Scheie syndrome

IDUAAlpha-L-iduronidase

KOKnockout

DEXADual-Energy X-ray Absorptiometry analysis

BMDBone Mineral Density

BMCBone Mineral Contents

ERTEnzyme Replacement Therapy

GAGsGlycosaminoglycans

ESEmbryonic Stem

Chihwa Kim and Min Jung Kwak contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s13023-015-0337-3 contains supplementary material, which is available to authorized users.

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Author: Chihwa Kim - Min Jung Kwak - Sung Yoon Cho - Ah-ra Ko - Jinguen Rheey - Jeong-Yi Kwon - Yokyung Chung - Dong-Kyu Jin

Source: https://link.springer.com/



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