Inhibin and premature ovarian failure.
BACKGROUND
Elucidation of the causes of premature ovarian failure (POF) is difficult due to the heterogeneity of the condition. Inhibin is a potential candidate gene for POF based on its dual actions on FSH secretion by the pituitary and gametogenesis in the gonads. A missense mutation in the inhibin alpha subunit gene (INHA G769A) is associated with POF in several populations. However, there is phenotypic heterogeneity in INHA G769A mutation carriers.


METHODS
Relevant studies were identified by searching PubMed and mutational frequencies combined for meta-analysis.


RESULTS
Meta-analysis of published studies revealed a risk difference of 0.04 (-0.030 to 0.11). The occurrence of asymptomatic carriers in populations suggests incomplete penetrance and/or a multi-genetic cause of POF. We propose that a decline in inhibin bioactivity caused by the mutation could increase FSH levels; and in a susceptible individual, the heightened sensitivity to gonadotrophins causes POF. Impaired paracrine effects of inhibin could impact folliculogenesis due to reduced antagonism of activin, bone morphogenetic protein 15 and growth differentiation factor 9. Functional studies of this mutation indicate normal production of dimeric inhibin A and B and impaired bioactivity of inhibin B.


CONCLUSIONS
The identification of an autosomal mutation in the inhibin alpha subunit gene that is significantly linked to POF in certain ethnic populations highlights the role of inhibin in the regulation of ovarian biology and fertility. Although the reduction of inhibin B bioactivity by the INHA G769A mutation is clearly not the only cause, evidence suggests that this change may serve as a susceptibility factor, increasing the likelihood of POF.
Chand
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Prince Henry's Institute of Medical Research, Clayton, VIC 3168, Australia. ashwini.chand@princehenrys.org
Harrison
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Shelling
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D000595:Amino Acid Sequence; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007265:Inhibins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000175:diagnosis / Q000235:genetics*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D007265:Inhibins