Novel inactivating mutations in the FSH receptor cause premature ovarian insufficiency with resistant ovary syndrome

Research question: What is the genetic aetiology of three resistant ovary syndrome (ROS) pedigrees from 13 Chinese Han families with non-syndromic premature ovarian insufficiency (POI). Design: The proband in each family was subjected to whole-exome sequencing. Bioinformatic and in-vitro functional analyses were performed for the functional characterization of the FSHR mutations. Results: Four novel mutations, two homozygous mutations (c.419delA, c.1510C>T), and a compound heterozygous mutation (c.44G>A and deletion of exons 1 and 2) of FSHR were identified in the three non-syndromic POI-with-ROS families. Bioinformatic analysis predicted that the three novel point mutations in FSHR are deleterious and associated with POI in the three families, which was confirmed by in-vitro functional analysis, in which FSH-induced adenosine 3', 5'-cyclic monophosphate production was abolished for all receptors. Conclusions: The three novel point mutations in FSHR were all functional inactivating mutations, and were the genetic aetiology of the three non-syndromic POI-with-ROS families. The first FSHR frameshift mutation is reported here, and the first missense mutation in the signal peptide-encoding region of FSHR to be associated with POI. Women affected by ROS should consider undergoing mutation screening for FSHR.