Identification and characterization of novel compound heterozygous variants in FSHR causing primary ovarian insufficiency with resistant ovary syndrome

Front Endocrinol (Lausanne). 2023 Jan 10:13:1013894. doi: 10.3389/fendo.2022.1013894. eCollection 2022.


Primary ovarian insufficiency (POI) is among the foremost causes of women infertility due to premature partial or total loss of ovarian function. Resistant ovary syndrome (ROS) is a subtype of POI manifested as normal ovarian reserve but insensitive to gonadotropin stimulation. Inactivating variants of follicle-stimulating hormone receptor (FSHR), a class A G-protein coupled receptor, have been associated with POI and are inherited via an autosomal recessive pattern. In this study, we investigated the genetic causes of a primary infertility patient manifested as POI with ROS, and elucidated the structural and functional impact of variants of uncertain significance. Next-generation sequencing (NGS) combined with Sanger sequencing revealed novel compound heterozygous FSHR variants: c.1384G>C/p.Ala462Pro and c.1862C>T/p.Ala621Val, inherited from her father and mother, respectively. The two altered amino acid sequences, localized in the third and seventh transmembrane helix of FSHR, were predicted as deleterious by in silico prediction. In vitro experiments revealed that the p.Ala462Pro variant resulted in barely detectable levels of intracellular signaling both in cAMP-dependent CRE-reporter activity and ERK activation and displayed a severely reduced plasma membrane receptor expression. In contrast, the p.Ala621Val variant resulted in partial loss of receptor activation without disruption of cell surface expression. In conclusion, two unreported inactivating FSHR variants potentially responsible for POI with ROS were first identified. This study expands the current phenotypic and genotypic spectrum of POI.

Keywords: compound heterozygous variant; follicle-stimulating hormone receptor; primary ovarian insufficiency; resistant ovary syndrome; transmembrane helix.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Genotype
  • Humans
  • Infertility, Female*
  • Primary Ovarian Insufficiency* / genetics
  • Primary Ovarian Insufficiency* / metabolism
  • Reactive Oxygen Species
  • Receptors, FSH / genetics
  • Receptors, FSH / metabolism


  • Receptors, FSH
  • Reactive Oxygen Species

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (81701460 to XC), General Research Program for Medicine and Health of Zhejiang Province (2020KY414 to JS, 2019KY021 to RW, and 2020KY448 to XC), Natural Science Foundation of Zhejiang Province (LY20H160046 to LY, LQ19H040005 to BJ), and Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, P. R. China (ZDFY2020-RG-0006 to XC).