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Identification and in vitro characterization of follicle stimulating hormone (FSH) receptor variants associated with abnormal ovarian response to FSH.

ABSTRACT: FSH mediates cyclic follicle growth and development and is widely used for controlled ovarian stimulation in women undergoing infertility treatment. The ovarian response of women to FSH is variable, ranging from poor response to ovarian hyperstimulation.We investigated whether genetic alterations of the FSH receptor (FSHR) contribute to this variability.Our approach was to study women undergoing treatment with in vitro fertilization falling into the edges of the normal distribution of ovarian response to FSH, with respect to age.We conducted the study at the Yale Fertility Clinic.We extracted RNA from cumulus cells surrounding the oocytes of women undergoing in vitro fertilization and analyzed the FSHR mRNA by RT-PCR and sequencing.We identified four abnormal FSHR splicing products (three exon deletions and one intron insertion) in the FSHR mRNA in 37% (13 of 35) of women tested. All alterations affected the extracellular ligand-binding portion of the receptor without causing a frameshift. When transfected in HEK293T cells, all four splicing variants showed markedly decreased cAMP activation compared to controls. Untransfected cells showed no response to FSH, whereas all the cell lines showed normal cAMP activation when treated with forskolin, a nonreceptor-mediated cAMP stimulant. None of the normal or mutant forms showed any response to LH or TSH.Our findings strongly indicate FSHR variants as being an intrinsic genetic cause of some forms of infertility and identify a need for functional characterization of these variants and the investigation of more individualized ovarian stimulation protocols.

SUBMITTER: Gerasimova T

PROVIDER: S-EPMC2840851 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Identification and in vitro characterization of follicle stimulating hormone (FSH) receptor variants associated with abnormal ovarian response to FSH.

Gerasimova Tsilya T Thanasoula Maria N MN Zattas Dimitrios D Seli Emre E Sakkas Denny D Lalioti Maria D MD

The Journal of clinical endocrinology and metabolism 20100108 2

<h4>Context</h4>FSH mediates cyclic follicle growth and development and is widely used for controlled ovarian stimulation in women undergoing infertility treatment. The ovarian response of women to FSH is variable, ranging from poor response to ovarian hyperstimulation.<h4>Objective</h4>We investigated whether genetic alterations of the FSH receptor (FSHR) contribute to this variability.<h4>Design and patients</h4>Our approach was to study women undergoing treatment with in vitro fertilization f ...[more]

PMID: 20061434

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Project description:Genes critical for fertility are highly conserved in mammals. Interspecies DNA sequence variation, resulting in amino acid substitutions and post-transcriptional modifications, including alternative splicing, are a result of evolution and speciation. The mammalian follicle-stimulating hormone receptor (FSHR) gene encodes distinct species-specific forms by alternative splicing. Skipping of exon 2 of the human FSHR was reported in women of North American origin and correlated with low response to ovarian stimulation with exogenous follicle-stimulating hormone (FSH). To determine whether this variant correlated with low response in women of different genetic backgrounds, we performed a blinded retrospective observational study in a Turkish cohort. Ovarian response was determined as low, intermediate or high according to retrieved oocyte numbers after classifying patients in four age groups (<35, 35-37, 38-40, >40). Cumulus cells collected from 96 women undergoing IVF/ICSI following controlled ovarian hyperstimulation revealed four alternatively spliced FSHR products in seven patients (8%): exon 2 deletion in four patients; exon 3 and exons 2 + 3 deletion in one patient each, and a retention of an intron 1 fragment in one patient. In all others (92%) splicing was intact. Alternative skipping of exons 2, 3 or 2 + 3 were exclusive to low responders and was independent of the use of agonist or antagonist. Interestingly, skipping of exon 3 occurs naturally in the ovaries of domestic cats--a good comparative model for human fertility. We tested the signaling potential of human and cat variants after transfection in HEK293 cells and FSH stimulation. None of the splicing variants initiated cAMP signaling despite high FSH doses, unlike full-length proteins. These data substantiate the occurrence of FSHR exon skipping in a subgroup of low responders and suggest that species-specific regulation of FSHR splicing plays diverse roles in mammalian ovarian function.

Dataset Information

Identification and in vitro characterization of follicle stimulating hormone (FSH) receptor variants associated with abnormal ovarian response to FSH.

Publications

Identification and in vitro characterization of follicle stimulating hormone (FSH) receptor variants associated with abnormal ovarian response to FSH.

Similar Datasets

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