Germline analysis of the ACVR1B gene as a candidate gene for ovarian failure. H. Dixit¹, K.L. Rao¹, J. Nair², V.V. Padmalatha¹, M.K. Kanakavalli¹, M. Deenadayal³, N. Gupta⁴, B.N. Chakrabarty⁴, L. Singh¹. 1) Centre for Cellular and Molecular Biology, Hyderabad, Andhra Pradesh, India; 2) Vellore Institute of Technology, Vellore, Tamil Nadu, India; 3) Infertility Institute and Research Centre, Hyderabad, Andhra Pradesh, India; 4) Institute of Reproductive Medicine, Kolkata, West Bengal, India.
   An amenorrhoea (>6 months) with elevated FSH levels before 40 years is defined as premature ovarian failure (POF). Elevation of FSH levels results in depletion of ovarian follicles. Activins up-regulate FSH production by activating its Type II and Type I receptors located on gonadotrophs. Activated Type I receptor (ACVR1B) sends intracellular signaling for FSH upregulation. The loss of function mutations in this gene cause carcinomas due to loss of growth inhibitory effect of activin. We hypothesize that gain of function mutations in this receptor gene may cause ovarian failure due to constitutive or increased FSH production. These mutations can result in either activin independent form of receptor or its increased sensitivity for activin binding. Case control study was performed by DNA sequencing analysis for coding regions (9 exons) of ACVR1B gene. A total of 196 ovarian failure cases including 133 POF cases, 63 pri. amenorrhoea (PA) cases and 200 control were recruited. All individuals were chromosomally normal and their recruitment followed strict medical norms. Sequence analysis of ACVR1B gene revealed 7 novel variants and 3 documented variants. Three novel missense variants c.392T>G, c.505T>G, c.581G>A were exclusively associated with patients while completely absent in controls. The c.392T>G (p.Iso131Ser) variant was revealed in 7/133 POF cases (p value=0.0015) and 4/63 PA cases (p value=0.003). The c.505T>G (p.Cys169Gly) was present in a POF patient. The c.581G>A (p.Gly194Glu) variant was present in 4/133 cases of POF (p value=0.025). Preliminary analysis showed gain of function nature of these variants. Frequency of an intronic variant c.332-155_332-154insA was higher in patients (12.2%) than controls (5%) (p value=0.012). This is first report presenting gain of function mutations in ACVR1B gene associated with ovarian failure.