Development of infertility at young adult age in a mouse model of human Sandhoff disease.

Sandhoff disease is a human lysosomal storage disease. In a knockout mouse model of Sandhoff disease, which lacks the beta-subunit of beta-hexosaminidase A (Hex A, alphabeta subunits) and B (Hex B, betabeta subunits), the mutant homozygous mice (Hexb(-/-)) are healthy until 15 weeks of age when they develop neurodegenerative symptoms. This study was designed to analyse the fertility profile of male and female Hexb(-/-) mice. Mating behaviour of Hexb(-/-) mice was assessed at different ages. The ovarian function of Hexb(-/-) females was determined by superovulation studies. The quality of spermatozoa and ova was assessed by an in vitro fertilization (IVF) procedure. Hexb(-/-) mice were fertile at a young age. Males were fertile up to the age of 69.3 +/- 6.3 days (mean +/- SD) and females were fertile up to the age of 56-63 days. Since both the Hexb (-/-) sexes showed fertility, the results indicate that Hex A and Hex B (major isozymes of beta-hexosaminidase) may not be required for sperm-ovum interactions, in contrast to the widely accepted belief. On the other hand, young adult Hexb(-/-) males showed a reduction in mating behaviour at the age of 84.8 +/- 2.2 days and an absence of mating behaviour at 94.2 +/- 2.0 days. Spermatozoa from Hexb(-/-) mice (aged 109.2 +/- 1.8 days) showed a lower IVF rate. Among Hexb (-/-) females aged 85.6 +/- 2.1 days, no mice became pregnant although they were positive for a vaginal plug when caged with fertile males. The number of ova recovered from Hexb(-/-) females (aged 111.0 +/- 3.1 days) and the IVF rate of ova were lower than those of controls. In conclusion, Hex A and Hex B may not be required for sperm-ovum interactions. Mice lacking Hex A and Hex B activities develop infertility at a young adult age in an age-dependent manner.