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Cardiac and ocular pathologies in a mouse model of mucopolysaccharidosis type VI
Oliver F Strauch1, Jörg Stypmann, Thomas Reinheckel
1Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
Abstract:
Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease caused by a deficiency of arylsulfatase B (ASB) which has its function in the sequential degradation of glycosaminoglycans (GAG). Targeted disruption of the ASB gene resulted in a mouse model of MPS VI that has been closely investigated for skeletal and chondral dysplasia. As ocular and cardiac impairment are also clinically important manifestations of the MPS VI syndrome, the present study was initiated for detailed biochemical, histologic and functional analysis of cornea, optic nerve and heart in ASB-deficient mice. Biochemical evidence for GAG-storage could be obtained for liver, kidney, spleen and myocardium as well as for heart valves, cornea and optic nerve from ASB-deficient mice. In MPS VI mice, histology revealed structural impairment of corneal stroma and epithelium as well as a thickening of the heart valves. According to histologic investigations, the optic nerve appeared not to be altered. However, GAG-storage in the dura mater could be demonstrated in MPS VI mice. Heart function was assessed by echocardiography. While the dimensions of MPS VI hearts were not altered, these hearts clearly showed decreased myocardial contraction and a 50% reduction of cardiac output. In addition, insufficiencies in the mitral and aortic valves were detected. Thus, ASB-deficient mice resemble the phenotype of human MPS VI not only in the skeletal but also in the ocular and cardiac symptoms. To our knowledge, these in vivo evaluations of heart function represent the first respective investigation of a MPS VI animal model and should provide a valuable measure for therapy studies in the MPS VI mouse.
Insights
Mucopolysaccharidosis type VI (MPS VI) mouse models show glycosaminoglycan storage in ocular and cardiac tissues. These mice exhibit impaired heart function and valve issues, mirroring human MPS VI symptoms for therapeutic studies.
Area of Science:
- Biochemistry
- Genetics
- Pathology
Background:
- Mucopolysaccharidosis type VI (MPS VI) is a genetic lysosomal storage disease.
- It results from a deficiency in arylsulfatase B (ASB), crucial for glycosaminoglycan (GAG) degradation.
- Existing MPS VI mouse models primarily focus on skeletal issues.
Purpose of the Study:
- To investigate ocular and cardiac manifestations in ASB-deficient (MPS VI) mice.
- To perform detailed biochemical, histologic, and functional analyses of the cornea, optic nerve, and heart.
- To establish the validity of this mouse model for MPS VI research.
Main Methods:
- Biochemical analysis for GAG storage in various tissues.
- Histological examination of cornea, optic nerve, and heart structures.
- Echocardiography to assess cardiac function and dimensions.
Main Results:
- GAG storage confirmed in liver, kidney, spleen, myocardium, heart valves, cornea, and optic nerve.
- Histology showed corneal structural damage and thickened heart valves.
- Echocardiography revealed reduced myocardial contraction and cardiac output, with mitral and aortic valve insufficiencies.
Conclusions:
- ASB-deficient mice exhibit ocular and cardiac phenotypes consistent with human MPS VI.
- This model accurately reflects skeletal, ocular, and cardiac symptoms of MPS VI.
- The study provides the first in vivo cardiac function evaluation in an MPS VI mouse model, valuable for therapeutic research.