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

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 α-L-iduronidase deficiency. α-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 α-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.

Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies

“…IDUA encodes a glycosyl hydrolase that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate (49) . Wang et al (2010) (50) created Idua-W392X mouse model, and found that 35-week-old homozygous Idua-W392X mice showed a 24% increase in femur BMD, and bone abnormalities such as thickening of the zygomatic arch and aberrations in the length and width of the femur were also observed (50) .…”

Effect of Readthrough Treatment in Fibroblasts of Patients Affected by Lysosomal Diseases Caused by Premature Termination Codons

“…To our knowledge, only one knock-in mouse model has been reported for the diseases studied herein [55]. Interestingly, in this particular model (mutation p.Trp392* of IDUA;…”

Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry

“…In contrast to the two previously reported Idua knock-out mouse models, Idua −/− and MPS I [13], [14], the Idua- W392X knock-in mouse model carries a nonsense mutation corresponding to the IDUA- W402X mutation, commonly found in Hurler syndrome patients [15]. Wang et al showed that the phenotype of Idua- W392X mouse model parallels that of human MPS I-H disease, which includes GAG accumulation due to loss of α-L-iduronidase activity, cardiac manifestations and bone abnormalities such as broadening of the face, thickening of the zygomatic arch and atypical femur length and width [15].…”

“…Wang et al showed that the phenotype of Idua- W392X mouse model parallels that of human MPS I-H disease, which includes GAG accumulation due to loss of α-L-iduronidase activity, cardiac manifestations and bone abnormalities such as broadening of the face, thickening of the zygomatic arch and atypical femur length and width [15]. Even though the existing animal models have been useful in evaluating various therapeutic approaches such as enzyme replacement therapy [16], bone marrow transplantation [17], [18], and gene therapy [19], [20], much of the molecular mechanisms leading to the pathology remain to be elucidated.…”