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A novel mucopolysaccharidosis type II mouse model with an iduronate-2-sulfatase-P88L mutation
Ryuichi Mashima1, Mari Ohira2, Torayuki Okuyama2,3
1Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. mashima-r@ncchd.go.jp.
Abstract:
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder characterized by an accumulation of glycosaminoglycans (GAGs), including heparan sulfate, in the body. Major manifestations involve the central nerve system (CNS), skeletal deformation, and visceral manifestations. About 30% of MPS II is linked with an attenuated type of disease subtype with visceral involvement. In contrast, 70% of MPS II is associated with a severe type of disease subtype with CNS manifestations that are caused by the human iduronate-2-sulfatase (IDS)-Pro86Leu (P86L) mutation, a common missense mutation in MPS II. In this study, we reported a novel Ids-P88L MPS II mouse model, an analogous mutation to human IDS-P86L. In this mouse model, a significant impairment of IDS enzyme activity in the blood with a short lifespan was observed. Consistently, the IDS enzyme activity of the body, as assessed in the liver, kidney, spleen, lung, and heart, was significantly impaired. Conversely, the level of GAG was elevated in the body. A putative biomarker with unestablished nature termed UA-HNAc(1S) (late retention time), one of two UA-HNAc(1S) species with late retention time on reversed-phase separation,is a recently reported MPS II-specific biomarker derived from heparan sulfate with uncharacterized mechanism. Thus, we asked whether this biomarker might be elevated in our mouse model. We found a significant accumulation of this biomarker in the liver, suggesting that hepatic formation could be predominant. Finally, to examine whether gene therapy could enhance IDS enzyme activity in this model, the efficacy of the nuclease-mediated genome correction system was tested. We found a marginal elevation of IDS enzyme activity in the treated group, raising the possibility that the effect of gene correction could be assessed in this mouse model. In conclusion, we established a novel Ids-P88L MPS II mouse model that consistently recapitulates the previously reported phenotype in several mouse models.
Insights
A novel mouse model for Mucopolysaccharidosis type II (MPS II) was developed, mimicking the human IDS-P86L mutation. This model shows impaired enzyme activity, elevated GAGs, and biomarker accumulation, aiding MPS II research.
Area of Science:
- Biochemistry
- Genetics
- Animal Models
Background:
- Mucopolysaccharidosis type II (MPS II) is a genetic lysosomal storage disorder.
- It involves glycosaminoglycan (GAG) accumulation, affecting the central nervous system (CNS) and skeletal structure.
- The severe form is often linked to the IDS-P86L mutation.
Purpose of the Study:
- To establish and characterize a novel mouse model for MPS II using an analogous mutation (Ids-P88L).
- To investigate the enzyme activity, GAG levels, and biomarker accumulation in this new model.
- To assess the potential of gene therapy for treating MPS II in this model.
Main Methods:
- Development of a novel Ids-P88L MPS II mouse model.
- Assessment of iduronate-2-sulfatase (IDS) enzyme activity in blood and various organs (liver, kidney, spleen, lung, heart).
- Quantification of GAG levels and the specific biomarker UA-HNAc(1S).
- Evaluation of nuclease-mediated genome correction for gene therapy.
Main Results:
- The Ids-P88L mouse model exhibited significantly impaired IDS enzyme activity and a reduced lifespan.
- Elevated GAG levels and accumulation of the UA-HNAc(1S) biomarker were observed, particularly in the liver.
- Gene therapy showed a marginal increase in IDS enzyme activity, suggesting potential for therapeutic assessment.
Conclusions:
- The novel Ids-P88L mouse model effectively recapitulates key features of human MPS II.
- This model serves as a valuable tool for studying MPS II pathogenesis and evaluating potential therapies.
- The findings support the investigation of gene correction strategies for MPS II.
