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

Brendan J. Houston, Anne E. O'Connor, Degang Wang, Georgia Goodchild, D. Jo Merriner, Haitong Luan, Don F. Conrad, Liina Nagirnaja, Kenneth I. Aston, Sabine Kliesch, Margot J. Wyrwoll, Corinna Friedrich, Frank Tuttelmann, Craig Harrison, Moira K. Obryan, Kelly Walton

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Testicular-derived inhibin B (α/β B dimers) acts in an endocrine manner to suppress pituitary production of follicle-stimulating hormone (FSH), by blocking the actions of activins (β A/B/β 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 (β 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 InhbbM364T/M364T mice, where mouse INHBB p.Met364 corresponds with human p.Met360. Surprisingly, we found that the testes of male InhbbM364T/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 InhbbM364T/M364T males compared to wildtype males. Despite this testis phenotype, male InhbbM364T/M364T mutant mice retained normal fertility. Serum hormone analyses, however, indicated that the InhbbM364T 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.

Original languageEnglish (US)
Article numberbqab269
Issue number3
StatePublished - Mar 1 2022


  • activin
  • follicle stimulating hormone
  • inhibin
  • male fertility
  • spermatogenesis
  • testis

ASJC Scopus subject areas

  • Endocrinology


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