Data from: A point mutation in an otherwise dispensable upstream Fshb enhancer moderately impairs fertility in female mice

Follicle-stimulating hormone (FSH) is necessary for fertility in both
sexes as a regulator of gametogenesis and hormone synthesis. Humans with
loss-of-function mutations within the gene encoding the FSH beta subunit
(FSHB) are infertile. Similarly, female Fshb knock-out mice are infertile
and fail to ovulate, and males are subfertile. We recently reported the
discovery and characterization of an upstream enhancer of FSHB located 26
Kb upstream of the transcriptional start site in humans (-17 Kb in mouse)
that also amplifies activin and gonadotropin-releasing hormone induction
of FSHB. Notably, the upstream enhancer contains a polymorphic,
fertility-associated site in humans, rs11031006 (G/A), and the minor
allele (A) increased enhancer activity in vitro as compared to the major
allele (G), likely by increasing the affinity of an SF1 binding element.
To investigate the role of the novel enhancer and rs11031006 variant in
vivo, we created mouse models to assess deletion of the upstream enhancer
and the impact of the G>A point mutation at the
rs11031006-equivalent base. A full characterization of the -17 Kb enhancer
deletion model revealed no apparent differences in fertility or serum
FSH/LH levels, nor did a larger deletion that also included an additional
putative regulatory element. In contrast, female mice homozygous for the
mutated A allele at the rs11031006-equivalent position had fewer litters
over a 120-day fertility assay, abnormal estrous cycling at 10 months, and
reduced pituitary Lhb transcript abundance. Overall, while the mouse -17
Kb Fshb enhancer is dispensable for fertility, the rs11031006-equivalent
G>A mutation results in subfertility in females.