Elevated Levels of FMR1 mRNA in Granulosa Cells Are Associated with Low Ovarian Reserve in FMR1 Premutation Carriers

Elizur, Shai E.; Lebovitz, Oshrit; Derech-Haim, Sanaz; Dratviman‐Storobinsky, Olga; Feldman, Baruch; Dor, Jehoshua; Orvieto, Raoul; Cohen, Yoram

doi:10.1371/journal.pone.0105121

Cited by 56 publications

(48 citation statements)

References 26 publications

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“…A recent suggestion that the accumulation of FMR1 mRNA in granulosa cells is cytotoxic (toxic RNA gain-of-function model) may perhaps enlighten us as to how the low ovarian reserve observed in premutated carriers could be the pathogenetic mechanism for ovarian insufficiency [25]. Interestingly, the authors found that the number of retrieved eggs after IVF was non-linearly associated to the number of CGG repeats in the range of premutation, having an unfavourable prognosis in the range 80-120 that in turn was non-linearly associated with the highest concentration of mRNA in granulosa cells.…”

Section: How Fmr1 Mutations Influence Different Phenotypesmentioning

confidence: 99%

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Noto

Harrity

Walsh

et al. 2016

J Assist Reprod Genet

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Purpose This is a comprehensive review of the literature in this field attempting to put the FMR1 gene and its evaluation into context, both in general and for the reproductive health audience. Methods Online database search of publications with systematic review of all papers relevant to ovarian reserve and assisted reproduction was done. Results Relevant papers were identified and assessed, and an attempt was made to understand, rationalize and explain the divergent views in this field of study. Seminal and original illustrations were employed. Conclusions FMR1 is a highly conserved gene whose interpretation and effect on outcomes remains controversial in the reproductive health setting. Recent re-evaluations of the commonly accepted normal range have yielded interesting tools for possibly explaining unexpected outcomes in assisted reproduction. Fragile X investigations should perhaps become more routinely assessed in the reproductive health setting, particularly following a failed treatment cycle where oocyte quality is thought to be a contributing factor, or in the presence of a surprise finding of diminished ovarian reserve in a young patient.

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Section: How Fmr1 Mutations Influence Different Phenotypesmentioning

confidence: 99%

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Noto

Harrity

Walsh

et al. 2016

J Assist Reprod Genet

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“…A similar negative correlation in oocyte yield was noted in our cohort of pre-mutation carriers with median CGG repeats of 91 (66-96). Interestingly, the FMR1 mRNA levels in the Elizur et al [29] study was significantly lower in pre-mutation carriers possessing lower or higher CGG repeats, with a non-linear relationship with oocyte yield. Despite the associations highlighted in the study, putative mechanisms of mRNA toxicity were not presented.…”

Section: Discussionmentioning

confidence: 76%

“…In humans, elevated FMR1 mRNA levels have been in noted in FMR1 premutation carriers [28] , suggesting that accumulation of FMR1 mRNA may be toxic to the human ovary. In a case-control study of 21 FMR1 pre-mutation carriers and 15 controls undergoing IVF, Elizur et al [29] highlighted that the highest FMR1 mRNA levels were found in the granulosa cells of pre-mutation carriers with midsize CGG repeats (80-120). Furthermore, the lowest number of oocytes retrieved was also from the same group, signifying a negative linear correlation between Data are presented as mean ± SD and n (%).…”

Section: Discussionmentioning

confidence: 99%

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Impact of <b><i>FMR1</i></b> Pre-Mutation Status on Blastocyst Development in Patients Undergoing Pre-Implantation Genetic Diagnosis

Hutchinson

Pereira

Lilienthal

et al. 2017

Gynecol Obstet Invest

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Background/Aims: The study aimed to investigate the impact of fragile X mental retardation 1 (FMR1) pre-mutation status on blastocyst development in patients undergoing pre-implantation genetic diagnosis (PGD). Methods: Case-control study of patients <40 years undergoing PGD at blastocyst stage for FMR1 pre-mutation status. Age-matched patients undergoing PGD for other single gene disorders were considered controls. Blastocyst development, calculated per metaphase II (MII) oocyte retrieved and per 2 pronuclear (2PN) embryos, was compared between the 2 groups. Pregnancy outcomes after embryo transfer were also compared. Results: Eighty-one and 791 patients were included in the FMR1 and control groups, respectively. FMR1 pre-mutation carriers had lower indicators of ovarian reserve, required higher gonadotropin doses, and had fewer MII oocytes retrieved. Mean blastocyst development per MII oocyte (12.6 vs. 29.4%; p < 0.001) and per 2PN embryos (21.5 vs. 41.7%; p < 0.001) was lower in the FMR1 group. An inverse correlation between the number of FMR1 CGG repeats and blastocyst development per MII oocyte (ρ = -0.63; p < 0.001) was observed. There was no difference in the rates of clinical pregnancy, spontaneous abortion, or live birth among the groups. Conclusion: Our study suggests lower rates of blastocyst development in patients with FMR1 pre-mutation status and an inverse correlation between the number of FMR1 CGG repeats and blastocyst development.

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“…As might be expected, the later development of POI has been linked to increased rates of uptake of fertility assistance, which are higher among PMCs with POI, compared to those without POI [46]. PMCs have also been observed to show a reduced response to ovarian hyperstimulation compared to the typical population [32]. …”

Section: Resultsmentioning

confidence: 99%

Endocrine Dysfunction in Female FMR1 Premutation Carriers: Characteristics and Association with Ill Health

Campbell

Eley

McKechanie

et al. 2016

Genes

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Female FMR1 premutation carriers (PMC) have been suggested to be at greater risk of ill health, in particular endocrine dysfunction, compared to the general population. We set out to review the literature relating to endocrine dysfunction, including premature ovarian insufficiency (POI), in female PMCs, and then to consider whether endocrine dysfunction in itself may be predictive of other illnesses in female PMCs. A systematic review and pilot data from a semi-structured health questionnaire were used. Medline, Embase, and PsycInfo were searched for papers concerning PMCs and endocrine dysfunction. For the pilot study, self-reported diagnoses in females were compared between PMCs with endocrine dysfunction (n = 18), PMCs without endocrine dysfunction (n = 14), and individuals without the premutation (n = 15). Twenty-nine papers were identified in the review; the majority concerned POI and reduced fertility, which are consistently found to be more common in PMCs than controls. There was some evidence that thyroid dysfunction may occur more frequently in subgroups of PMCs and that those with endocrine difficulties have poorer health than those without. In the pilot study, PMCs with endocrine problems reported higher levels of fibromyalgia (p = 0.03), tremor (p = 0.03), headache (p = 0.01) and obsessive–compulsive disorder (p = 0.009) than either comparison group. Further larger scale research is warranted to determine whether female PMCs are at risk of endocrine disorders other than those associated with reproduction and whether endocrine dysfunction identifies a high-risk group for the presence of other health conditions.

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Elevated Levels of FMR1 mRNA in Granulosa Cells Are Associated with Low Ovarian Reserve in FMR1 Premutation Carriers

Cited by 56 publications

References 26 publications

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Impact of <b><i>FMR1</i></b> Pre-Mutation Status on Blastocyst Development in Patients Undergoing Pre-Implantation Genetic Diagnosis

Endocrine Dysfunction in Female FMR1 Premutation Carriers: Characteristics and Association with Ill Health

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