| FMRP translational regulator 1 | OKDB#: 102 |
| Symbols: | FMR1 | Species: | human | ||
| Synonyms: | POF, FMRP, POF1, FRAXA | Locus: | Xq27.3 in Homo sapiens |
|
For retrieval of Nucleotide and Amino Acid sequences please go to:
OMIM
Entrez Gene
Mammalian Reproductive Genetics Endometrium Database Resource Orthologous Genes UCSC Genome Browser GEO Profiles new! Amazonia (transcriptome data) new! R-L INTERACTIONS MGI |
| General Comment |
Genetic insights into biological mechanisms governing human ovarian ageing. Ruth KS et al. (2021) Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.//////////////////X-linked mental retardation associated with marXq28, or fragile X syndrome, is characterized by moderate to severe mental retardation, macroorchidism, large ears, prominent jaw, and high-pitched jocular speech. Expression is variable, with mental retardation being the most common feature. This phenotype is associated with mutations in the FMR1 gene. Fragile X syndrome is caused by a large expansion of a (CGG)n repeat in the first exon of the FMR1 gene. ragile X syndrome occurs in all racial and ethnic groups, and it is a condition of major epidemiological importance among mentally handicapped males. The fragile X syndrome is due to the shutdown of the FMR1 gene transcription, and the pathogenesis of this syndrome is a consequence of absence of the protein product of the FMR1 gene.
Murray et al. (1998) screened 147 women with idiopathic premature ovarian failure and found a significant association with premutations in the FMR1 gene, with 6 women having premutations, including 4 familial and 2 sporadic cases, but no women with full mutations in the FMR1 gene. Murray et al. (1998) concluded that premutations of FMR1 can affect ovarian development.The fragile X premutation: into the phenotypic fold.
Hagerman RJ,et al reviewed the literature on POF and FMR1 premutation.
Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1) are known to contribute to the fragile X phenotype through genetic instability and transmission of full mutation alleles (>200 repeats). There is now mounting evidence that the premutation alleles themselves contribute to clinical involvement, including premature ovarian failure among female carriers and a new tremor/ataxia syndrome among older male carriers. The premutation is associated with an increase in FMR1 expression.
PGD for fragile X syndrome: ovarian function is the main determinant of success. Tsafrir A et al. BACKGROUND PGD for fragile X syndrome (FRAX) is inefficient, probably owing to fewer oocytes, poor embryo quality and difficulties in genetic analysis. We investigated IVF-PGD in FRAX mutation carriers compared with controls, looking at the effects of oocyte and embryo number/quality on live birth outcome. METHODS We performed IVF-PGD in 27 patients with the FRAX mutation and 33 controls with other genetic diseases. Genetic testing was by multiplex PCR. RESULTS Seventy-nine and 108 IVF-PGD cycles were started in FRAX mutation carriers and controls, respectively. Twenty-two patients had a premutation (CGG repeat number 60-200) and five had a full mutation (300-2000 CGG repeats). FRAX patients required higher doses of gonadotrophins (6788 +/- 2379 versus 4360 +/- 2330, P< 0.001) but had lower peak serum estradiol levels (8166 +/- 5880 versus 10 211 +/- 4673, P = 0.03) and fewer oocytes retrieved (9.8 +/- 6 versus 14 +/- 8, P = 0.01). The cancelation rate (unsatisfactory ovarian response) was higher in the FRAX group than in the control group (13 versus 1%, P < 0.001). When embryos were transferred, ongoing pregnancy/live birth rates per transfer were similar (29 versus 36%, P = 0.54). CONCLUSIONS Ovarian dysfunction in FRAX carriers is more prevalent and profound than previously appreciated, with a high cancelation rate and reduced efficiency of PGD. The main determinant for successful PGD for FRAX is ovarian dysfunction. When embryo transfer is possible, the results are comparable to PGD for other monogenic diseases.
NCBI Summary: The protein encoded by this gene binds RNA and is associated with polysomes. The encoded protein may be involved in mRNA trafficking from the nucleus to the cytoplasm. A trinucleotide repeat (CGG) in the 5' UTR is normally found at 6-53 copies, but an expansion to 55-230 repeats is the cause of fragile X syndrome. Expansion of the trinucleotide repeat may also cause one form of premature ovarian failure (POF1). Multiple alternatively spliced transcript variants that encode different protein isoforms and which are located in different cellular locations have been described for this gene. [provided by RefSeq, May 2010] |
||||
| General function | Cell proliferation | ||||
| Comment | Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI). Sherman SL 2014 et al. Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP's function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI. ///////////////////////// The RNA-binding Proteins FMR1, Rasputin and Caprin Act Together with the UBA Protein Lingerer to Restrict Tissue Growth in Drosophila melanogaster. Baumgartner R 2013 et al. Appropriate expression of growth-regulatory genes is essential to ensure normal animal development and to prevent diseases like cancer. Gene regulation at the levels of transcription and translational initiation mediated by the Hipo and Insulin signaling pathways and by the TORC1 complex, respectively, has been well documented. Whether translational control mediated by RNA-binding proteins contributes to the regulation of cellular growth is less clear. Here, we identify Lingerer (Lig), an UBA domain-containing protein, as growth suppressor that associates with the RNA-binding proteins Fragile X mental retardation protein 1 (FMR1) and Caprin (Capr) and directly interacts with and regulates the RNA-binding protein Rasputin (Rin) in Drosophila melanogaster. lig mutant organs overgrow due to increased proliferation, and a reporter for the JAK/STAT signaling pathway is upregulated in a lig mutant situation. rin, Capr or FMR1 in combination as double mutants, but not the respective single mutants, display lig like phenotypes, implicating a redundant function of Rin, Capr and FMR1 in growth control in epithelial tissues. Thus, Lig regulates cell proliferation during development in concert with Rin, Capr and FMR1. ///////////////////////// The KH motif has been identified in single or multiple copies in a number of RNA associated proteins. Adinolfi et al. (1999) reviewed the knowledge accumulated about the sequence, structure, and functions of the KH. The multidomain architecture of most of the KH-containing proteins inspired an approach based on the production of peptides spanning the sequence of an isolated KH motif. The presence of the KH motifs in fmr1, the protein responsible for the fragile X syndrome, and their possible role in the fmr1 functions were discussed. | ||||
| Cellular localization | Cytoplasmic | ||||
| Comment | FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve. Rehnitz J et al. (2018) Fragile-X-Mental-Retardation-1- (FMR1)-gene is supposed to be a key gene for ovarian reserve and folliculogenesis. It contains in its 5'-UTR a triplet-base-repeat (CGG), that varies between 26 and 34 in general population. CGG-repeat-lengths with 55-200 repeats (pre-mutation = PM) show instable heredity with a tendency to increase and are associated with premature-ovarian-insufficiency or failure (POI/POF) in about 20%. FMR1-mRNA-expression in leucocytes and granulosa cells (GCs) increases with CGG-repeat-length in PM-carriers, but variable FMR1-expression profiles were also described in women with POI without PM-FMR1 repeat-length. Additionally, associations between low numbers of retrieved oocytes and elevated FMR1-expression levels have been shown in GCs of females with mid-range PM-CGG-repeats without POI. Effects of FMR1-repeat-lengths-deviations (n < 26 or n > 34) below the PM range (n < 55) on ovarian reserve and response to ovarian stimulation remain controversial. We enrolled 229 women undergoing controlled ovarian hyperstimulation for IVF/ICSI-treatment and devided them in three ovarian-response-subgroups: Poor responder (POR) after Bologna Criteria, polycystic ovary syndrome (PCO) after Rotterdam Criteria, or normal responder (NOR, control group). Subjects were subdivided into six genotypes according to their be-allelic CGG-repeat length. FMR1-CGG-repeat-length was determined using ALF-express-DNA-sequencer or ABI 3100/3130 × 1-sequencer. mRNA was extracted from GCs after follicular aspiration and quantitative FMR1-expression was determined using specific TaqMan-Assay and applying the ΔΔCT method. Kruskall-Wallis-Test or ANOVA were used for simple comparison between ovarian reserve (NOR, POR or PCO) and CGG-subgroups or cohort demographic data. All statistical analysis were performed with SPSS and statistical significance was set at p ≤ 0.05. A statistically significant increase in FMR1-mRNA-expression-levels was detected in GCs of PORs with heterozygous normal/low-CGG-repeat-length compared with other genotypes (p = 0.044). Female ovarian response may be negatively affected by low CGG-alleles during stimulation. In addition, due to a low-allele-effect, folliculogenesis may be impaired already prior to stimulation leading to diminished ovarian reserve and poor ovarian response. A better understanding of FMR1 expression-regulation in GCs may help to elucidate pathomechanisms of folliculogenesis disorders and to develop risk-adjusted treatments for IVF/ICSI-therapy. Herewith FMR1-genotyping potentially provides a better estimatation of treatment outcome and allows the optimal adaptation of stimulation protocols in future.////////////////// FMR1 gene CGG repeat variation within the normal range is not predictive of ovarian response in IVF cycles. Morin SJ et al. (2016) The relationship between FMR1 CGG premutation status and decreased ovarian responsiveness is well established. The association between FMR1 CGG repeat number in the currently defined normal range (less than 45 repeats) and ovarian reserve, however, is controversial. This retrospective study examined whether variation in CGG repeat number in the normal range was associated with markers of ovarian response in IVF cycles. The first IVF cycle of 3006 patients with FMR1 CGG repeat analysis was examined. Only patients carrying two alleles with less than 45 CGG repeats were included for analysis. The CGG repeat number furthest from the modal peak was plotted against number of mature oocytes retrieved and no correlation was identified. Patients were also separated into biallelic genotype groups, based on the recently proposed narrower "new normal" range of 26-34 CGG repeats. A linear regression showed that none of the biallelic genotype groups were associated with a decreased oocyte yield. The euploidy rates after comprehensive chromosomal screening were equivalent among the genotype groups. No difference was found in the rate of cycle cancellation for poor response. Despite increasing use, FMR1 CGG repeats in the normal range cannot be used as a predictor of ovarian response to gonadotrophin stimulation.////////////////// Zfrp8 forms a complex with fragile-X mental retardation protein and regulates its localization and function. Tan W et al. (2016) Fragile-X syndrome is the most commonly inherited cause of autism and mental disabilities. The Fmr1 (Fragile-X Mental Retardation 1) gene is essential in humans and Drosophila for the maintenance of neural stem cells, and Fmr1 loss results in neurological and reproductive developmental defects in humans and flies. FMRP (Fragile-X Mental Retardation Protein) is a nucleo-cytoplasmic shuttling protein, involved in mRNA silencing and translational repression. Both Zfrp8 and Fmr1 have essential functions in the Drosophila ovary. In this study, we identified FMRP, Nufip (Nuclear Fragile-X Mental Retardation Protein-interacting Protein) and Tral (Trailer Hitch) as components of a Zfrp8 protein complex. We show that Zfrp8 is required in the nucleus, and controls localization of FMRP in the cytoplasm. In addition, we demonstrate that Zfrp8 genetically interacts with Fmr1 and tral in an antagonistic manner. Zfrp8 and FMRP both control heterochromatin packaging, also in opposite ways. We propose that Zfrp8 functions as a chaperone, controlling protein complexes involved in RNA processing in the nucleus.////////////////// Prospectively assessing risk for premature ovarian senescence in young females: a new paradigm. Gleicher N et al. (2015) Approximately 10% of women suffer from premature ovarian senescence (POS), ca. 9% as occult primary ovarian insufficiency (OPOI, also called premature ovarian aging, POA) and ca. 1% as primary ovarian insufficiency (POI, also called premature ovarian failure, POF). In a large majority of cases POS is currently only diagnosed at advanced clinical stages when women present with clinical infertility. We here, based on published evidence, suggest a new diagnostic paradigm, which is based on identifying young women at increased risk for POS at much earlier stages. Risk factors for POS are known from the literature, and can be used to identify a sub-group of young women at increased risk, who then are followed sequentially with serial assessments of functional ovarian reserve (FOR) until a diagnosis of POS is either reached or refuted. At approximately 25% prevalence in general U.S. populations (and somewhat different prevalence rates in more homogenous Asian and African populations), so-called low (CGGn<26) mutations of the fragile X mental retardation 1 (FMR1) gene, likely, represents the most common known risk factor, including history-based risk factors from medical, genetic and family histories. Women so affirmatively diagnosed with POS at relative young ages, then have the opportunity to reconsider their reproductive planning and/or choose fertility preservation via oocyte or ovarian tissue cryopreservation at ages when such procedures are clinically much more effective and, therefore, also more cost-effective. Appropriate validation studies will have to precede widespread utilization of this paradigm.////////////////// | ||||
| Ovarian function | Germ cell development, Oogenesis, Oocyte maturation | ||||
| Comment | FMR1 and AKT/mTOR signalling pathways: potential functional interactions controlling folliculogenesis in human granulosa cells. Rehnitz J et al. (2017) Granulosa cells (GCs) play a major role in folliculogenesis and are crucial for oocyte maturation and growth. In these cells, the mTOR/AKT signalling pathway regulates early folliculogenesis by maintaining the dormancy of primordial follicles, while FSH induces their further differentiation and maturation. Because changes in number of CGG triplets in FMR1 exon 1 (below or beyond normal values of 26-34 triplets) affect ovarian reserve and pre-mutations containing >54 CGG triplets represent a known risk factor for premature ovarian insufficiency/failure, we investigated in the human GC model (COV434) how FMR1/FMRP and mTOR/AKT are expressed and potentially interact during GC proliferation. As FMR protein (FMRP) is expressed mainly in human ovarian GCs, we used these after inducing their proliferation using recombinant FSH (rFSH) and the repression of the mTOR/AKT signalling pathway. We showed that AKT and mTOR expression levels significantly increase after stimulation with rFSH, while S6K and FMR1 expression decrease. After inhibiting mTOR and AKT, FMR1 and S6K expression significantly increased. Only AKT inhibition led to decreased FMRP levels, as expected due to the known FMR1/FMRP negative feedback loop. But rFSH and the mTOR inhibition increased them, indicating a decoupling of this FMR1/FMRP negative feedback loop in our model system.////////////////// The ovarian response in fragile X patients and premutation carriers undergoing IVF-PGD: reappraisal. Avraham S et al. (2017) What is the association between the ovarian response and the number of CGG repeats among full mutation and premutation carriers of fragile X (FMR1), undergoing controlled ovarian hyperstimulation (COH) for PGD? Ovarian response was normal in full mutation patients but decreased in premutation carriers, although the number of repeats was not statistically significantly associated with the number of oocytes retrieved. There is inconsistent data in the literature regarding ovarian response in FMR1 carriers. Studies exploring the ovarian response of full mutation patients are lacking. Retrospective study, a university affiliated tertiary hospital, IVF unit, PGD referral center. We examined the medical records of all women undergoing fresh IVF-PGD cycles due to fragile X. Data recorded included demography, duration of stimulation, amount of gonadotropins administered, number of dominant follicles, maximal E2 levels and number of oocytes retrieved. Data were analyzed using univariate and multivariate mixed models. P-values <0.05 were considered significant. Data were collected from the medical records of 21 patients with a full mutation on the FMR1 gene and 51 premutation carriers. Overall 309 fresh cycles were analyzed. Premutation carriers displayed reduced ovarian response, as demonstrated by fewer oocytes retrieved. In contrast, full mutation patients had a normal response. Comparison of premutation carriers and full mutation patients showed: mean oocytes retrieved per cycle (8.4 ± 1.1 versus 14.1 ± 1.7, P = 0.005), lower levels of estradiol (E2; 1756 ± 177, versus 2928 ± 263, P = 0.0004), respectively. There was no significant difference between premutation carriers and full mutation patients in regard to fertilization rate, cleavage rate or biopsy rate. No correlation was found between the number of repeats in the premutation carriers and the number of oocytes retrieved or E2 levels. Age and the type of protocol were the only factors found to be in correlation with the number of the oocyte retrieved (P = 0.037, and P = 0.003, respectively) among the premutation carriers. Similarly, no association was found between the number of repeats and the fertilization rate, cleavage rate or biopsy rate among premutation carriers. We had a relatively low number of premutation carriers with >100 repeats, which made it challenging to draw a firm conclusions from this group. Physicians must address the increased risk for reduced ovarian response and primary ovarian insufficiency (POI) among carriers and consider surveillance of ovarian reserve markers. The last, might expedite family plans completion or fertility preservation. None.////////////////// Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency. Alvarez-Mora MI et al. (2015) FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation females carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways.////////////////// How the FMR1 gene became relevant to female fertility and reproductive medicine. Gleicher N 2014 et al. This manuscript describes the 6 year evolution of our center's research into ovarian functions of the FMR1 gene, which led to the identification of a new normal CGGn range of 26-34. This 'new' normal range, in turn, led to definitions of different alleles (haplotypes) based on whether no, one or both alleles are within range. Specific alleles then were demonstrated to represent distinct ovarian aging patterns, suggesting an important FMR1 function in follicle recruitment and ovarian depletion of follicles. So called low alleles, characterized by CGGn<26, appear associated with most significant negative effects on reproductive success. Those include occult primary ovarian insufficiency (OPOI), characterized by prematurely elevated follicle stimulating hormone (FSH) and prematurely low anti-Mllerian hormone, and significantly reduced clinical pregnancy rates in association with in vitro fertilization (IVF) in comparison to women with normal (norm) and high (CGGn>34) alleles. Because low FMR1 alleles present in approximately 25% of all females, FMR1 testing at young ages may offer an opportunity for earlier diagnosis of OPOI than current practice allows. Earlier diagnosis of OPOI, in turn, would give young women the options of reassessing their reproductive schedules and/or pursue fertility preservation via oocyte cryopreservation when most effective. ///////////////////////// The FMR1 gene, infertility, and reproductive decision-making: a review. Pastore LM 2014 et al. The strongest association between FMR1 and the ovary in humans is the increased risk of premature ovarian failure (POF) in women who carry the premutation level of CGG repeats (55-199 CGGs). Research on the FMR1 gene has extended to other endpoints of relevance in the OB/GYN setting for women, including infertility and ovarian hormones. After reviewing the nomenclature changes that have occurred in recent years, this article reviews the evidence linking the length of the FMR1 repeat length to fertility and ovarian hormones (follicle stimulating hormone and anti-mullerian hormone as the primary methods to assess ovarian reserve in clinical settings). The literature is inconsistent on the association between the FMR1 trinucleotide repeat length and infertility. Elevated levels of follicle stimulating hormone have been found in women who carry the premutation; however the literature on the relationship between anti-mullerian hormone and the CGG repeat length are too disparate in design to make a summary statement. This article considers the implications of two transgenic mouse models (FXPM 130R and YAC90R) for theories on pathogenesis related to ovarian endpoints. Given the current screening/testing recommendations for reproductive age females and the variability of screening protocols in clinics, future research is recommended on pretest and posttest genetic counseling needs. Future research is also needed on ovarian health measurements across a range of CGG repeat lengths in order to interpret FMR1 test results in reproductive age women; the inconsistencies in the literature make it quite challenging to advise women on their risks related to FMR1 repeat length. ///////////////////////// Correlation of triple repeats on the FMR1 (fragile X) gene to ovarian reserve: A new infertility test? Gleicher N et al. Objective. To determine to what degree the number of triple Cytosine/Guanine/Guanine (CGG) repeats on the FMR1 (fragile X) gene correlate with specific ovarian reserve parameters, and potentially facilitate infertility diagnosis. Design. Retrospective cohort study. Setting. Academically affiliated, private infertility center in New York City. Population. One hundred fifty-eight consecutive women, presenting to an infertility center. Methods. Triple CGG repeat counts on the FMR1 gene were correlated with baseline follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH), and compared to the distribution reported in the literature for general populations. Main outcome measures. Distribution of CGG counts in infertile vs. general populations and correlation between CGG counts and ovarian reserve parameters. Results. Infertile women demonstrated in both FMR1 alleles a mild shift toward higher CGG counts. In the investigated range up to 55 CGG repeats, counts inversely correlated with AMH (R (2)=0.21; p<0.001), though not with FSH, attributable to women <38 years (R (2)=0.26; p<0.001). Up to age 40, women with <35 triple repeats demonstrated higher AMH levels than those with 35-50 repeats (F (1, 87)=5.3, p=0.025). Counts between 35 and 50 repeats correlated inversely to AMH (R (2)=0.41; p<0.013). Conclusions. Premature ovarian senescence and infertility in ranges up to 55 triple CGG repeats are associated with increasing triple CGG numbers on the FMR1 gene. The number of CGG repeats on the FMR1 gene appears to represent a potentially useful new test in diagnosing risk toward diminished ovarian reserve and female infertility. Ovarian reserve determinations suggest new function of FMR1 (fragile X gene) in regulating ovarian ageing. Gleicher N et al. With regard to ovarian reserve, 26-34 triple CGG repeats on the FMR1 gene denote 'normal'. This study explores whether two-allele analyses reflects risk towards diminished ovarian reserve based on age in consecutive patients (34 oocyte donors and 305 infertility patients), longitudinally and cross-sectionally. Box and whisker plots confirmed the normal range of CGG counts. Patients were then defined as normal with both alleles in range, as heterozygous with one allele outside and as homozygous with both alleles outside of range. Ovarian reserve was assessed by anti-M?an hormone (AMH). Normals at young ages exhibited significantly higher AMH concentrations than either heterozygous or homozygous females (P=0.009). By approximately age 35, heterozygous women have higher AMH concentrations than normal women, while homozygous women exceed normal women shortly before age 50years. These data support a control function of the FMR1 gene over ovarian reserve, thus defining life-long ovarian reserve patterns. Heterozygous and homozygous abnormal CGG counts reduce ovarian reserve at younger ages and improve ovarian reserve at older ages. They, thus, at expense of reduced fertility in the young, preserve fertility into older age. This function of potential evolutionary importance may explain the preservation of the FMR1 gene despite its, at times, severe neuropsychiatric risks. | ||||
| Expression regulated by | |||||
| Comment | |||||
| Ovarian localization | Oocyte, Granulosa, Theca | ||||
| Comment | Necrosectomy and postoperative local lavage in necrotizing pancreatitis. Beger HG et al. (1988) Necrosectomy with postoperative continuous local lavage was performed in a prospective study involving 95 patients with necrotizing pancreatitis. In the same period 567 patients with oedematous-interstitial pancreatitis were treated non-operatively with a hospital mortality rate of 0.7 per cent. In patients with necrotizing pancreatitis the median Ranson criteria score was 4.5 points; operation was required at a median of 7 days after the onset of symptoms because of non-response to conservative treatment. In all, 59 per cent of the patients (56 out of 95) developed extended intrapancreatic parenchymal necrosis, 70 per cent had ascites, and 66 per cent had intra- and extrapancreatic necrosis; 42 per cent of the patients had bacterial infection of the necrotic tissue. For lavage a median of 8 l/24 h of fluid were instilled postoperatively for 25 days (median). The lavage fluid showed high levels of immunoreactive trypsin, phospholipase A2, and endotoxin in the early postoperative period. Hospital mortality rate was 8.4 per cent. Necrosectomy and continuous postoperative lavage can achieve high survival rates in patients with necrotizing pancreatitis. Postoperative local lavage allows the continuous non-operative evacuation of biologically active compounds and devitalized tissue, and avoids damage to remaining vital exocrine and endocrine pancreatic tissue.//////////////////Epigenetic Aberration of FMR1 Gene in Infertile Women with Diminished Ovarian Reserve. Eslami H et al. (2018) The diminished ovarian reserve (DOR) is a condition characterized by a reduction in the number and/or quality of oocytes. This primary infertility disorder is usually accompanied with an increase in the follicle-stimulating hormone (FSH) levels and regular menses. Although there are many factors contributing to the DOR situation, it is likely that many of idiopathic cases have genetic/epigenetic bases. The association between the FMR1 premutation (50-200 CGG repeats) and the premature ovarian failure (POF) suggests that epigenetic disorders of FMR1 can act as a risk factor for the DOR as well. The aim of this study was to analyze the mRNA expression and epigenetic alteration (histone acetylation/methylation) of the FMR1 gene in blood and granulosa cells of 20 infertile women. In this case-control study, these women were referred to the Royan Institute, having been clinically diagnosed as DOR patients. Our control group consisted of 20 women with normal antral follicle numbers and serum FSH level. All these women had normal karyotype and no history of genetic disorders. The number of CGG triplet repeats in the exon 1 of the FMR1 gene was analyzed in all samples. Results clearly demonstrated significantly higher expression of the FMR1 gene in blood and granulosa cells of the DOR patients with the FMR1 premutation compared to the control group. In addition, epigenetic marks of histone 3 lysine 9 acetylation (H3K9ac) and di-metylation (H3K9me2) showed significantly higher incorporations in the regulatory regions of the FMR1 gene, including the promoter and the exon 1, whereas tri-metylation (H3K9me3) mark showed no significant difference between two groups. Our data demonstrates, for the first time, the dynamicity of gene expression and histone modification pattern in regulation of FMR1 gene, and implies the key role played by epigenetics in the development of the ovarian function.////////////////// FMR1 and AKT/mTOR signalling pathways: potential functional interactions controlling folliculogenesis in human granulosa cells. Rehnitz J et al. (2017) Granulosa cells (GCs) play a major role in folliculogenesis and are crucial for oocyte maturation and growth. In these cells, the mTOR/AKT signalling pathway regulates early folliculogenesis by maintaining the dormancy of primordial follicles, while FSH induces their further differentiation and maturation. Because changes in number of CGG triplets in FMR1 exon 1 (below or beyond normal values of 26-34 triplets) affect ovarian reserve and pre-mutations containing >54 CGG triplets represent a known risk factor for premature ovarian insufficiency/failure, we investigated in the human GC model (COV434) how FMR1/FMRP and mTOR/AKT are expressed and potentially interact during GC proliferation. As FMR protein (FMRP) is expressed mainly in human ovarian GCs, we used these after inducing their proliferation using recombinant FSH (rFSH) and the repression of the mTOR/AKT signalling pathway. We showed that AKT and mTOR expression levels significantly increase after stimulation with rFSH, while S6K and FMR1 expression decrease. After inhibiting mTOR and AKT, FMR1 and S6K expression significantly increased. Only AKT inhibition led to decreased FMRP levels, as expected due to the known FMR1/FMRP negative feedback loop. But rFSH and the mTOR inhibition increased them, indicating a decoupling of this FMR1/FMRP negative feedback loop in our model system.////////////////// The Stage- and Cell Type-Specific Localization of Fragile X Mental Retardation Protein in Rat Ovaries. Takahashi N et al. (2015) Premutations of the fragile X mental retardation 1 (FMR1) gene are associated with increased risk of primary ovarian insufficiency. Here we examined the localization of the Fmr1 gene protein product, fragile X mental retardation protein (FMRP), in rat ovaries at different stages, including fetus, neonate, and old age. In ovaries dissected from 19 days postcoitum embryos, the germ cells were divided into 2 types: one with decondensed chromatin in the nucleus was FMRP positive in the cytoplasm, but the other with strongly condensed chromatin in the nucleus was FMRP negative in the cytoplasm. The FMRP was predominantly localized to the cytoplasm of oocytes in growing ovarian follicles. Levels of FMRP in oocytes from elderly (9 or 14 months of age) ovaries were lower than in those from younger ovaries. These results suggest that FMRP is associated with the activation of oogenesis and oocyte function. Especially, FMRP is likely to be implicated in germline development during oogenesis.////////////////// Elevated Levels of FMR1 mRNA in Granulosa Cells Are Associated with Low Ovarian Reserve in FMR1 Premutation Carriers. Elizur SE 2014 et al. AIM To assess the role of mRNA accumulation in granulosa cells as the cause of low ovarian response among FMR1 premutation carriers undergoing pre-implantation genetic diagnosis (PGD). DESIGN Case control study in an academic IVF unit. Twenty-one consecutive FMR1 premutation carriers and 15 control women were included. After oocyte retrieval the granulosa cells mRNA levels of FMR1 was measured using RT-PCR. RESULTS In FMR1 premutation carriers, there was a significant non-linear association between the number of CGG repeats and the number of retrieved oocytes (p<0.0001) and a trend to granulosa cells FMR1 mRNA levels (p?=?0.07). The lowest number of retrieved oocytes and the highest level of mRNA were seen in women with mid-size CGG repeats (80-120). A significant negative linear correlation was observed between the granulosa cells FMR1 mRNA levels and the number of retrieved oocytes (R2 linear?=?0.231, P?=?0.02). CONCLUSION We suggest that there is a no-linear association between the number of CGG repeats and ovarian function, resulting from an increased granulosa cells FMR1 mRNA accumulation in FMR1 carriers in the mid-range (80-120 repeats). ///////////////////////// Expression of fragile X mental retardation protein (FMRP) and Fmr1 mRNA during folliculogenesis in the rat. Ferder I et al. Fragile X mental retardation protein belongs to a small family of RNA-binding proteins. Its absence or inactivity is responsible for Fragile X Syndrome, the most common cause of inherited mental retardation. Despite its ubiquitous expression, FMRP function and expression remain almost understudied in non-neuronal tissues, though previous studies on germline development during oogenesis may suggest a special function of this protein also in ovarian tissue. In addition, the well documented association of FMR1 premutation state with Fragile X-related Premature Ovarian Insufficiency adds interest to the role of FMRP in ovarian physiology. The aim of the present work was to investigate the expression of Fmr1 mRNA and its protein, FMRP, at different stages of rat follicular development. By immnuhistochemical studies, we demonstrated FMRP expression in granulosa, theca and the germ cell in all stages of follicular development. In addition, changes in Fmr1 expression, both at the protein and mRNA levels, were observed. FMRP levels increased upon follicular development, while preantral and early antral follicles presented similar levels of Fmr1 transcripts, with decreased expression in preovulatory follicles. These observations suggest that Fmr1 expression in the ovary is regulated at different and perhaps independent levels. In addition, our results also show expression of at least four different isoforms of FMRP during all stages of follicular growth, with expression patterns which differ from those observed in brain and testis. Our study shows a regulated expression of Fmr1, both at mRNA and protein levels, during rat follicular development. Tissue-specific expression of a FMR1/beta-galactosidase fusion gene in transgenic mice. Hergersberg M et al. Fragile X syndrome is one of the most common genetic causes of mental retardation, yet the mechanisms controlling expression of the fragile X mental retardation gene FMR1 are poorly understood. To identify sequences regulating FMR1 transcription, transgenic mouse lines were established using a fusion gene consisting of an E.coli beta-galactosidase reporter gene (lacZ) linked to a 2.8 kb fragment spanning the 5'-region of FMR1. Five transgenic mouse lines showed lacZ expression in brain, in particular in neurons of the granular layer of the cerebellum. Expression of the reporter gene was also detected in Leydig cells and spermatogonia in the testis, in many epithelia of adult mice, and in the two other steroidogenic cell types, adrenal cortex cells and ovarian follicle cells. Embryonic tissues which showed strong activity of the reporter gene included the telencephalon, the genital ridge, and the notochord. This expression pattern closely resembles the endogenous one, indicating that the 5' FMR1 gene promoter region used in this study contains most cis-acting elements regulating FMR1 transcription. Variable expression of the Fragile X Mental Retardation 1 (FMR1) gene in patients with premature ovarian failure syndrome is not dependent on number of (CGG)n triplets in exon 1. Schuettler J et al. BACKGROUND Increased expression of the Fragile X Mental Retardation 1 (FMR1) gene in blood cells has been claimed to be associated with variable (CGG)(n) triplet numbers in the 5' untranslated region of this gene. Increased CGG triplet numbers, including that of the so-called premutation range (n= 55-200), were shown to have a risk of <26% to impair ovarian reserve leading to primary ovarian insufficiency and premature ovarian failure (POF). METHODS DNA and RNA samples were isolated from 74 patients with idiopathic POF to evaluate quantitatively the expression of FMR1 in leukocytes and CGG triplet number on FMR1 gene alleles. mRNA levels were normalized and compared with those of control women. Expression of the encoded protein (FMRP) was analysed by immunohistochemistry on ovarian biopsy tissue sections. RESULTS A large variance of the FMR1 transcript level was found in the leukocyte RNA samples, but only in patients with POF, and this variability did not correlate to variance of CGG triplet numbers found on both FMR1 alleles (19 < n> 90). During normal folliculogenesis, FMRP is predominantly expressed in granulosa cells. CONCLUSIONS Our data suggest that FMR1 expression during human folliculogenesis is probably a quantitative trait. Proper function of FMRP in granulosa cells seems to depend on an optimal transcript level. All women with CGG triplet numbers outside the range associated with normal folliculogenesis (26 < n> 34) are therefore expected to have a relaxed FMR1 transcription control. FMR1 transcript levels in leukocytes might therefore be diagnostic for altered FMRP levels in granulosa cells, which will affect the process of folliculogenesis. | ||||
| Follicle stages | Primary, Secondary, Antral, Preovulatory | ||||
| Comment | Enhanced expression of the murine FMR1 gene during germ cell proliferation suggests a special function in both the male and the female gonad. B?ner D et al. To elucidate the function of the FMR1 gene, we applied RNA in situ hybridization to cryosections of mice from different developmental stages. The murine Fmr-1 was found transcribed in a ubiquitous manner with an expression pattern similar to glyceraldehyd phosphate dehydrogenase, Gapdh, which was used as a control gene. A significant difference in the Fmr-1 expression pattern, however, was markedly enhanced expression specifically confined to the testis and the fetal ovary. In the immature and mature testis an elevated level of Fmr-1 expression is found in type A1 spermatogonia. Expression in the testis is observed in fetal life, reaches the highest level in the immature testis, and declines early in adult life. In the mature ovary no specific Fmr-1 expression signal was found but enhanced levels were seen in the fetal ovary. At this developmental stage proliferation of oogonia takes place. It is suggested that FMR1 serves a special function during germ cell proliferation in males and females. These findings are discussed in the light of the current observation that fragile X patients produce only sperm with a premutation sized allele. Two hypotheses are put forward: (1) In males lack of FMR1 function results in a premeiotic defect preventing spermatogonia with a full mutation to reach meiosis. A fragile X mutation can be passed on to offsprings only as a premutation (selection hypothesis). (2) Transition of a premutation allele to full mutation occurs in a postzygotic stage after separation of the germ line and is restricted to soma cells (restriction hypothesis). Expression of FMR1 in proliferating germ cells is in line with both hypothesis. | ||||
| Phenotypes |
POF (premature ovarian failure) |
||||
| Mutations |
11 mutations
Species: human
Species: human
Species: human
Species: human
Species: human
Species: human
Species: mouse
Species: human
Species: mouse
Species: human
Species: human
|
||||
| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
| Links |
|
| created: | Sept. 1, 1999, midnight | by: |
Hsueh email:
home page: |
| last update: | Aug. 18, 2021, 11:22 a.m. | by: | hsueh email: |
Click here to return to gene search form