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

Reprod Biomed Online. 2019 Mar;38(3):397-406. doi: 10.1016/j.rbmo.2018.11.011. Epub 2018 Dec 8.


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.

Keywords: FSHR gene; Frameshift mutation; Novel mutation; Premature ovarian insufficiency; Resistant ovary syndrome.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Animals
  • CHO Cells
  • Cricetulus
  • Family
  • Female
  • Humans
  • Mutation, Missense*
  • Pedigree
  • Primary Ovarian Insufficiency / genetics*
  • Receptors, FSH / genetics*


  • Receptors, FSH