The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

A genetic mutation in the inhibin βB-subunit disrupts uterine function in mice (#144)

Kelly L Walton 1 , Helena Parkington 1 , Degang Wang 1 2 , Don Conrad 3 , Ki Aston 4 , Georgia Goodchild 1 , Ranga Siriwardhana 1 , Harold Coleman 1 , Craig Harrison 1 , Moira O'Bryan 1
  1. Monash University, Clayton, VIC, Australia
  2. Prenatal Diagnosis Center, Boai Hospital of Zhongshan , Guangdong, China
  3. Department of Genetics, Washington University School of Medicine, Washington, USA
  4. University of Utah School of Medicine, Utah, USA

Gonadal function is coordinated by pituitary hormones, including follicle stimulating hormone (FSH), which travel via the circulation to the ovaries and testes to drive folliculogenesis and spermatogenesis. In response to FSH stimulation, the gonads produce inhibin A and inhibin B, which act back at the pituitary to down-regulate FSH production. Inhibins (α/β dimers) block FSH release indirectly by antagonizing the actions of the related activins (β/β dimers) on the surface of pituitary cells. This circulatory hypothalamic-pituitary-gonadal (HPG) loop is integral to reproductive function, and consequently, imbalances in inhibin/activin can impact fertility. In a recent study, a homozygous genetic mutation (c.T1079C:p.M360T) arising from uniparental disomy of chromosome 2, was identified in the Inhbb gene (encodes the β-subunit of inhibin B and activin B) in a male patient suffering infertility (azoospermia). In the current study, we aimed to determine the impact of the InhbbM360Tmutation on the function of activin B and inhibin B. Mechanistic analysis revealed that the M360T mutation resulted in increased in vitro production of both activin B and inhibin B, but had no effect on the bioactivity of these proteins. To ascertain if the M360T mutation was sufficient to disrupt fertility, we generated InhbbM360T/M360Tmice. Although anything resembling azoospermia was not observed in male mice, we found that female InhbbM360T/M360T mice had a significant reproductive phenotype. Indeed pregnant InhbbM360T/M360T mice displayed abnormal labours (>8 hours) and increased litter sizes (up to 14 pups/litter). Serum hormone analyses support that the InhbbM360Tmutation likely disrupts the HPG axis, and may result in a hormonal imbalance in pregnant InhbbM360Tfemales.  Our InhbbM360T mouse represents a unique model to study failure to progress in labour.