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Cited by 62Lysosomal Storage Disorders ResearchGlycogen Storage Diseases and MyoclonusMetabolism and Genetic Disorders

Characterization of an MPS I-H knock-in mouse that carries a nonsense mutation analogous to the human IDUA-W402X mutation

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Wang, Dan, Shukla, Charu, Liu, Xiaoli, Schoeb, Trenton R., Clarke, Lorne A., Bedwell, David M., Keeling, Kim M.·2010·Molecular Genetics and Metabolism
DOI 10.1016/j.ymgme.2009.08.002PMC PMC2795040
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Abstract

Here we report the characterization of a knock-in mouse model for the autosomal recessive disorder mucopolysaccharidosis type I-Hurler (MPS I-H), also known as Hurler syndrome. MPS I-H is the most severe form of alpha-l-iduronidase deficiency. alpha-l-iduronidase (encoded by the IDUA gene) is a lysosomal enzyme that participates in the degradation of dermatan sulfate and heparan sulfate. Using gene replacement methodology, a nucleotide change was introduced into the mouse Idua locus that resulted in a nonsense mutation at codon W392. The Idua-W392X mutation is analogous to the human IDUA-W402X mutation commonly found in MPS I-H patients. We found that the phenotype in homozygous Idua-W392X mice closely correlated with the human MPS I-H disease. Homozygous W392X mice showed no detectable alpha-l-iduronidase activity. We observed a defect in GAG degradation as evidenced by an increase in sulfated GAGs excreted in the urine and stored in multiple tissues. Histology and electron microscopy also revealed evidence of GAG storage in all tissues examined. Additional assessment revealed bone abnormalities and altered metabolism within the Idua-W392X mouse. This new mouse will provide an important tool to investigate therapeutic approaches for MPS I-H that cannot be addressed using current MPS I-H animal models.

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  • Similar to patients with MPS-IH, Idua-W392X mice have undetectable α-L-iduronidase (IDUA) enzyme activity and elevated tissue glycosaminoglycans (GAGs).

    “Similar to patients with MPS-IH, Idua-W392X mice have undetectable α-L- iduronidase (IDUA) enzyme activity and elevated tissue glycosaminoglycans (GAGs) (32).”

    From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [32]

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Authors
Wang, D., Shukla, C., Liu, X., Schoeb, T. R., Clarke, L. A., Bedwell, D. M., & Keeling, K. M.
Affiliations
  • University of Alabama at Birmingham (US)
  • University of British Columbia (CA)
Corresponding author
Keeling, Kim M.
ORCID
Venue
Molecular Genetics and Metabolism
Publisher
Elsevier BV
Published
2010-01
Volume
99
Issue
1
Pages
62-71
ISSN
1096-7192 (ISSN-L)
DOI
10.1016/j.ymgme.2009.08.002
PMC
PMC2795040
OpenAlex
W2142776719
Cited by
62
References
0
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 10 · 2022: 10 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 3 · 2016: 1 · 2015: 4 · 2014: 1 · 2013: 4 · 2012: 2
FWCI
1.26
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Molecular Genetics and Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5p60dk079626-05)
  • National Cancer Institute (P30CA013148)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK-079626, P30DK056336)
  • National Institute of Neurological Disorders and Stroke (R01NS057412, P30NS057098)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR046031, P30AR048311)
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
Hurler syndrome, alpha-L-iduronidase deficiency, IDUA gene, knock-in mice, nonsense mutation, gene replacement, glycosaminoglycan storage, dermatan sulfate, heparan sulfate, lysosomal enzyme deficiency, bone abnormalities, animal models
MeSH terms
Animals, Disease Models, Animal, Femur, Glycosaminoglycans, Humans, Iduronidase, Mucopolysaccharidosis I, Liver, Mice, Inbred Strains, Mice, Transgenic, Microscopy, Electron, Spleen, Absorptiometry, Photon, Bone Density, Gene Expression Regulation, Enzymologic, Survival Analysis, Codon, Nonsense, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Mice

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