Abstract
Mice with mucopolysaccharidosis type VII (MPS VII) are devoid of β-glucuronidase and accumulate glycosaminoglycans in lysosomes resulting in bone dysplasia, learning disabilities, and decreased mobility. MPS VII males do not breed and, while MPS VII females occasionally mate with heterozygous males, they do not maintain their young postnatally. Heterozygous matings produce less than 25% MPS VII offspring, but until now it was unclear whether this results from prenatal or postnatal losses. The administration of recombinant β-glucuronidase from birth significantly reduces glycosaminoglycan storage in most tissues, increases life span, and improves the animal's cognitive ability and mobility. To determine whether reproductive failure is corrected by such therapy, male and female MPS VII mice were injected with enzyme at weekly intervals from birth to 5 wk of age (6xinj). Enzyme-replaced MPS VII mice bred when mated together. The 6xinj MPS VII males mated repeatedly until they were killed 135 d postinjection. All mated 6xinj MPS VII females gave birth to two litters, but maintained few of their young. Selective loss of MPS VII offspring was observed in matings between heterozygotes. Analysis of 379 preterm fetuses from heterozygous matings showed a frequency of 24.6% MPS VII pups, indicating that the decreased number of MPS VII pups produced by mating heterozygotes results from postnatal losses. The ovaries of young adult MPS VII mice have follicles and corpora lutea, and the testes generate sperm. Results suggest that the reproductive failure in MPS VII mice is related to impaired mobility and/or impaired cognitive function, and enzyme replacement restores mating capacity.
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Abbreviations
- GUS:
-
β-glucuronidase
- MPS VII:
-
mucopolysaccharidosis type VII
- GAG:
-
glycosaminoglycan
- ERT:
-
enzyme replacement therapy
- 6xinj:
-
six enzyme injections
- 2xinj:
-
two enzyme injections
- dpc:
-
days postconception
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Acknowledgements
The authors thank Drs. John Eppig and Wesley Beamer for critical review of the manuscript, Dr. Patricia Farrar for reviewing the gonadal histology, and Brenda Sprague for both mouse colony maintenance and performing the in utero experiments.
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Supported by an NSRA DK09570 to B.W.S.; R01s DK41082, DK27726, and HL49525 to J.E.B.
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Soper, B., Pung, A., Vogler, C. et al. Enzyme Replacement Therapy Improves Reproductive Performance in Mucopolysaccharidosis Type VII Mice But Does Not Prevent Postnatal Losses. Pediatr Res 45, 180–186 (1999). https://doi.org/10.1203/00006450-199902000-00004
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DOI: https://doi.org/10.1203/00006450-199902000-00004
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