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.