Human INHBB Gene Variant (c.1079T>C:p.Met360Thr) Alters Testis Germ Cell Content, but Does Not Impact Fertility in Mice

Testicular-derived inhibin B (alpha/beta (B) dimers) acts in an endocrine manner to suppress pituitary production of follicle-stimulating hormone (FSH), by blocking the actions of activins (beta (A/B)/beta (A/B) dimers). Previously, we identified a homozygous genetic variant (c.1079T>C:p.Met360Thr) arising from uniparental disomy of chromosome 2 in the INHBB gene (beta (B)-subunit of inhibin B and activin B) in a man suffering from infertility (azoospermia). In this study, we aimed to test the causality of the p.Met360Thr variant in INHBB and testis function. Here, we used CRISPR/Cas9 technology to generate Inhbb(M364T/M364T) mice, where mouse INHBB p.Met364 corresponds with human p.Met360. Surprisingly, we found that the testes of male Inhbb(M364T/M364T) mutant mice were significantly larger compared with those of aged-matched wildtype littermates at 12 and 24 weeks of age. This was attributed to a significant increase in Sertoli cell and round spermatid number and, consequently, seminiferous tubule area in Inhbb(M364T/M364T) males compared to wildtype males. Despite this testis phenotype, male Inhbb(M364T/M364T) mutant mice retained normal fertility. Serum hormone analyses, however, indicated that the Inhbb(M364T) variant resulted in reduced circulating levels of activin B but did not affect FSH production. We also examined the effect of this p.Met360Thr and an additional INHBB variant (c.314C>T: p.Thr105Met) found in another infertile man on inhibin B and activin B in vitro biosynthesis. We found that both INHBB variants resulted in a significant disruption to activin B in vitro biosynthesis. Together, this analysis supports that INHBB variants that limit activin B production have consequences for testis composition in males.

Automated summary

This study reveals the impact of INHBB gene variants on testis composition in males, particularly those that limit activin B production. Although the variants result in significantly larger testes, they do not affect fertility.