Introduction: Women carriers of premutations in the FMR1 gene are at higher risk of ovarian dysfunction and premature ovarian failure (POF). We hypothesize that high FMR1 expression in granulosa-cumulus cells (GrCCs) may be implicated in ovarian dysfunction.
Aims:To compare FMR1-mRNA levels in GrCCs and peripheral lymphocytes (PLs) of FRAX premutation carriers vs. controls and to correlate ovarian reserve with FMR1 transcript levels.
Materials and methods: Fourteen premutation carriers (mean age 31.57±3.18y) undegoing PGD at the Shaare-Zedek Medical Center were compared to 46 age-matched control women undergoing PGD for other non-expansion monogenic disorders. FMR1 mRNA expression levels in PLs and GrCCs were assessed by QPCR and droplet digital PCR, respectively. Ovarian reserve markers were measured at day 3. Ovarian response to stimulation was determined by maximal estradiol levels and the number of oocytes and mature (M2) oocytes retrieved.
Results: Mean FMR1 expression in PLs from the study group (0.18±0.06) was significantly higher than that of the controls (0.13±0.03), p = 0.002. A significant negative correlation was found between FMR1 mRNA expression in PLs and maximal estradiol levels and oocytesand M2 oocytes numbers (pp = 0.029.
Conclusions: Although the findings of elevated mRNA transcript levels in peripheral lymphocytes in FRAX carriers support the hypothesis of "mRNA gain of toxicity" as a contributor to POF, our findings of decreased mRNA expression in granulosa-cumulus cells conflict with this theory. FMR1-transcripts in other ovarian cells or other mechanisms may induce ovarian dysfunction in these women. The negative correlation between ovarian response and FMR1-transcript levels support the assumption that this mRNA may universally modulate ovarian function.
