Functional analysis of the human inhibin α subunit variant A257T and its potential role in premature ovarian failure

Ashwini L. Chand, Guck T. Ooi, Craig A. Harrison, Andrew N. Shelling, David M. Robertson

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)

Abstract

BACKGROUND: A nucleotide substitution in the inhibin α subunit (INHA 769G>A, A257T) has been associated with premature ovarian failure (POF). We hypothesize this mutation causes a reduction in inhibin bioactivity, removing its suppression on the pituitary FSH secretion. The aim of this study is to establish if A257T inhibin has reduced bioactivity. METHODS: Mouse LβT2 pituitary gonadotrope, human granulosa (COV434) and human embryonic kidney (HEK293) cells were co-transfected with an activin-responsive reporter and increasing amounts of wild-type or variant A257T inhibin α subunit, and the degree of inhibin antagonism of activin signalling determined. RESULTS: A 5-fold inhibition was observed with wild-type inhibin α subunit overexpression (P <0.001) (confirmed in HEK293 cells), while the A257T inhibin showed no inhibitory activity. In human ovarian COV434 transfected cells, while wild-type and A257T inhibin A had similar bioactivities, there was a significant reduction in the bioactivity of A257T inhibin B compared with wild-type inhibin B (P <0.005). In all the three cell systems, overexpression of wild-type and A257T α subunit resulted in a 2- to 6-fold increase in secretion of dimeric inhibin indicating the reduced inhibin response was not due to a failure of dimerization. CONCLUSIONS: This study supports the hypothesis that the INHA 769G>A variant may increase susceptibility to POF with impaired inhibin B bioactivity and provides insight into the complex aetiology of POF.

Original languageEnglish
Pages (from-to)3241-3248
Number of pages8
JournalHuman Reproduction
Volume22
Issue number12
DOIs
Publication statusPublished - Dec 2007
Externally publishedYes

Keywords

  • Activin
  • Inhibin A
  • Inhibin B
  • Inhibin in vitro bioactivity
  • Premature ovarian failure

Cite this