A Point Mutation in an Otherwise Dispensable Upstream Fshb Enhancer Moderately Impairs Fertility in Female Mice

Area of Science:

• Reproductive biology
• Endocrinology
• Genetics

Background:

• Follicle-stimulating hormone (FSH) is crucial for fertility, regulating gametogenesis and hormone synthesis in both sexes.
• Loss-of-function mutations in the FSH beta subunit (FSHB) gene cause infertility in humans and impact fertility in mice.
• A previously identified upstream enhancer of FSHB contains a human fertility-associated polymorphism, rs11031006 (G/A).

Purpose of the Study:

• To investigate the in vivo role of the novel FSHB upstream enhancer and the rs11031006 variant in fertility.
• To assess the impact of deleting the -17 Kb enhancer in mice.
• To determine the effect of the G>A point mutation equivalent to rs11031006 on female reproductive function.

Main Methods:

• Generation of mouse models with targeted deletion of the -17 Kb FSHB enhancer.
• Creation of mouse models with a G>A point mutation at the rs11031006-equivalent position.
• Fertility assays, estrous cycling analysis, and measurement of pituitary Lhb transcript abundance in genetically modified mice.

Main Results:

• Deletion of the -17 Kb FSHB enhancer, or a larger deletion including an adjacent regulatory element, did not affect fertility or serum FSH/LH levels in mice.
• Female mice homozygous for the rs11031006-equivalent G>A mutation exhibited reduced litter numbers over a 120-day fertility assay.
• These female mice also displayed abnormal estrous cycling and reduced pituitary Lhb transcript levels.

Conclusions:

• The -17 Kb FSHB enhancer is not essential for fertility in mice.
• The rs11031006-equivalent G>A mutation in the FSHB enhancer leads to subfertility in female mice.
• This variant may impact female reproductive health by affecting estrous cycling and Lhb expression.