Effects of a mutation in the transmembrane and coiled-coil domains 2 gene on ovarian function and reproductive aging

A mutation in the transmembrane and coiled-coil domain 2 (TMCO2) gene was identified in a family with premature ovarian insufficiency (POI). To determine whether the TMCO2 mutation causes the decline in ovarian function, Tmco2-deficient mice were bred and studied.

The F2 generation of Tmco2-deficient mice was obtained, and the breeding outcomes were assessed. Physical characteristics of the female mice were observed. White fat, ovarian tissue, and serum from Tmco2 heterozygous female mice were collected at 8, 18, and 28 weeks of age. Follicle counts and hormone levels were measured and analyzed.

(1) The birth rate of Tmco2^-/- mice was only 4.26%. (2) At 28 weeks of age, the Lee index and the adiposity index of Tmco2^+/- female mice were higher than those of Tmco2^+/+ (P = 0.0197 and 0.0180). (3) At 8 and 18 weeks of age, Tmco2^+/- mice had more secondary follicles than Tmco2^+/+ (P = 0.0159 and 0.0238). At 18 weeks, Tmco2^+/- had more small antral follicles than Tmco2^+/+ (P = 0.0317). However, at 28 weeks, Tmco2^+/- had fewer resting follicles and secondary follicles than Tmco2^+/+ (P = 0.0397 and 0.0238). (4) The AMH levels of Tmco2^+/- female mice peaked at 18 weeks. Their average FSH level at 28 weeks was significantly higher than that of Tmco2^+/+ (P = 0.0289).

The inheritance pattern of Tmco2^-/- mice was sublethal. The deficiency of Tmco2 adversely affected the growth and development of female mice. Tmco2^+/- female mice experienced decreased ovarian reserve and advancing reproductive aging. The TMCO2 mutation in humans may lead to POI.