Related Experiment Videos
Enzyme replacement therapy improves reproductive performance in mucopolysaccharidosis type VII mice but does not
B W Soper1, A W Pung, C A Vogler
1The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Abstract:
Mice with mucopolysaccharidosis type VII (MPS VII) are devoid of beta-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 beta-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.
Insights
Enzyme replacement therapy in mucopolysaccharidosis type VII (MPS VII) mice improved mobility and cognitive function. This treatment restored reproductive capacity in MPS VII mice, indicating postnatal losses are the primary cause of reproductive failure.
Area of Science:
- Genetics
- Biochemistry
- Reproductive Biology
Background:
- Mucopolysaccharidosis type VII (MPS VII) in mice results from a deficiency in beta-glucuronidase, leading to glycosaminoglycan accumulation.
- Affected mice exhibit bone dysplasia, cognitive deficits, reduced mobility, and reproductive failure.
- Previous studies showed enzyme replacement therapy (ERT) improves physical and cognitive symptoms but its effect on reproduction was unknown.
Purpose of the Study:
- To investigate the impact of early-life enzyme replacement therapy on the reproductive capacity of MPS VII mice.
- To determine whether reproductive failure in MPS VII mice is due to prenatal or postnatal losses.
Main Methods:
- MPS VII mice received weekly injections of recombinant beta-glucuronidase from birth to 5 weeks of age.
- Reproductive success was assessed by mating enzyme-replaced MPS VII mice together and analyzing offspring from heterozygous matings.
- Prenatal losses were quantified by examining fetuses from heterozygous matings.
Main Results:
- Enzyme-replaced MPS VII mice successfully mated and reproduced.
- Analysis of heterozygous matings revealed no significant prenatal loss of MPS VII fetuses (24.6% frequency).
- MPS VII females, while able to give birth, had poor postnatal survival of their young.
Conclusions:
- Reproductive failure in MPS VII mice is primarily due to postnatal losses, not prenatal factors.
- Enzyme replacement therapy effectively restores mating capacity in MPS VII mice.
- Impaired mobility and cognitive function likely contribute to reproductive failure in untreated MPS VII mice.