Mol. Hum. Reprod. Advance Access originally published online on January 3, 2006
Molecular Human Reproduction 2005 11(11):779-784; doi:10.1093/molehr/gah219
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INHA promoter polymorphisms are associated with premature ovarian failure
1Department of Obstetrics and Gynaecology, 2Department of Molecular Medicine, University of Auckland, Auckland, New Zealand, 3Department of Obstetrics and Gynaecology, University Medical Centre, Ljubljana, Slovenia and 4Department of Medicine and Bioregulatory Science (Third Department of Internal Medicine), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
5 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, Private Bag 92019, University of Auckland, Auckland, New Zealand. E-mail: a.shelling{at}auckland.ac.nz
Inhibin is an important glycoprotein that is involved in folliculogenesis. INHA, the gene encoding the inhibin alpha subunit, was recently proposed as a candidate for premature ovarian failure (POF), a syndrome that leads to the cessation of ovarian function under the age of 40 years. 70 POF patients and 70 controls were screened for the previously identified INHA –16C>T transition mutation. The T allele was found in 31/70 (44.3%) of controls, but only 18/70 (25.7%) of POF patients. This result indicates that the T allele is significantly underrepresented in the POF patient population (Fisher’s exact test, two-tail: P = 0.033). Sequence analysis of the INHA promoter in 50 POF patients and 50 controls identified a highly polymorphic imperfect TG repeat at approximately –300 bp, that consisted of four common haplotypes (A, B, C and D). The –16T allele is linked to the shortest repeat haplotype (haplotype C). Despite the association between haplotype C and POF, no significant difference was found between the promoter activity of a luciferase reporter construct containing haplotype C, and most of the other haplotypes tested. Interestingly, haplotype B failed to show any promoter activity. We conclude that the inheritance of specific INHA promoter haplotypes predispose to the development of premature ovarian failure.
Key words: infertility/inhibin/polymorphism/ovarian failure/TG repeat
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