A novel homozygous mutation in the FSHR gene is causative for primary ovarian insufficiency.

OBJECTIVE: To identify the potential FSHR mutation in a Chinese woman with primary ovarian insufficiency (POI).

DESIGN: Genetic and functional studies.

SETTING: University-based reproductive medicine center.

PATIENT(S): A POI patient, her family members, and another 192 control women with regular menstruation.

INTERVENTION(S): Ovarian biopsy was performed in the patient. Sanger sequencing was carried out for the patient, her sister, and parents. The novel variant identified was further confirmed with the use of control subjects.

MAIN OUTCOME MEASURE(S): Sanger sequencing and genotype analysis to identify the potential variant of the FSHR gene; hematoxylin and eosin staining of the ovarian section to observe the follicular development; Western blotting and immunofluorescence to detect FSH receptor (FSHR) expression; and cyclic adenosine monophosphate (cAMP) assay to monitor FSH-induced signaling.

RESULT(S): Histologic examination of the ovaries in the patient revealed follicular development up to the early antral stage. Mutational screening and genotype analysis of the FSHR gene identified a novel homozygous mutation c.175C>T (p.R59X) in exon 2, which was inherited in the autosomal recessive mode from her heterozygous parents but was absent in her sister and the 192 control women. Functional studies demonstrated that in vitro the nonsense mutation caused the loss of full-length FSHR expression and that p.R59X mutant showed no response to FSH stimulation in the cAMP level.

CONCLUSION(S): The mutation p.R59X in FSHR is causative for POI by means of arresting folliculogenesis.