Hum. Reprod. Advance Access originally published online on October 11, 2007
Human Reproduction 2007 22(12):3241-3248; doi:10.1093/humrep/dem323
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Functional analysis of the human inhibin 
subunit variant A257T and its potential role in premature ovarian failure
1 Prince Henry’s Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia 2 Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
3 Correspondence address. Tel: 613-9594-3221; Fax: 613-9594-6125; E-mail: ashwini.chand{at}princehenrys.org
BACKGROUND: A nucleotide substitution in the inhibin 
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 L
T2 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 subunit, and the degree of inhibin antagonism of activin signalling determined.
RESULTS: A 5-fold inhibition was observed with wild-type inhibin 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 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.
Key words: inhibin A/inhibin B/inhibin in vitro bioactivity/premature ovarian failure/activin
Submitted on May 23, 2007; resubmitted on September 12, 2007; accepted on September 17, 2007.
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