SELECTED ORAL COMMUNICATION SESSION, SESSION 51: (EPI) GENETICS, Tuesday 5 July 2011 17:00 - 18:00

The Fragile X Mental Retardation 1 (FMR1) gene encodes an RNA binding protein (FMRP) on the long arm of the human X chromosome (Xq27). It is functional in the cellular RISC (RNA-Induced Silencing Complex) which controls the cellular micro-RNA metabolism, thus the level of translation of multiple cellular transcripts (Jin et al. 2004). In men, dysfunction of FMR1 causing absence or reduction of the cellular FMRP amount induce the "Fragile X syndrome" (FXS: OMIM-ID: #300624), a severe neurological disorder, respectively, the "Fragile X-associated tremor/ataxia syndrome" (FXTAS: OMIM-ID: #300623), the most frequent late-onset neurodegenerative disorder. In women, reduction of the cellular FMRP amount can induce premature ovarian insufficiency (POI) and -failure (POF; OMIM-ID: 311360), most likely depending on age (Gleicher et al. 2010). Reduced FMRP levels in blood cells were found to be associated with a variable number of (CGG) n triplets in the 5untranslated region (UTR) of FMR1 exon 1 causing reduced or increased FMR1 transcript levels (Chen et al. 2003). We, therefore set out to compare the transcriptional FMR1 activity in the leukocytes of patients with POI/POF and in women with normal menstruation cycle and explore expression of FMRP in ovarian tissue sections. Material and Methods: 120 patients enrolling consecutively in our endocrinological outpatient clinic were selected for presence of "idiopathic" POI/POF syndrome with aid of an extensive clinical questionnaire. Patients with putative history of autoimmune diseases, or an iatrogenic background, respectively, with primary amenorrhea, or with karyotype abnormalities causing Turner Syndrome (45,X0) were excluded. The remaining "idiopathic" POI/POF patient subgroup included 74 individuals. With the same questionnaire 42 healthy women being over the age of 40 years with still regular menstruation or a physiologically conditioned menopause were selected as control group. DNA and RNA samples were isolated from their leukocytes to evaluate in parallel FMR1 expression by quantitative RT-PCR assays and the number of CGG triplets on both FMR1 gene alleles by sequence analyses. For immunohistochemical detection of FMRP in ovarian tissue sections we used a monoclonal FMRP antiserum with the standard APAAP protocol. CpG methylation analyses in FMR1 promoter subdomains were performed with an appropriate genomic bisulfit assay. Results: A large variance of the FMR1 transcript level was found in the leukocyte RNA samples but only in the POI/POF patient population. Surprisingly, this level was not associated with the variance of CGG triplet numbers found on both alleles of FMR1 exon 1 (1990). Some CGG triplet numbers in normal range were associated with a larger increase of FMR1 expression than found in the samples with a heterozygous CGG triplet number in the premutation range. In follicles of ovarian tissue sections FMRP is predominantly expressed in granulosa cells. Analyses of CpG methylation in FMR1 promoter subdomains (CpG island; FREE1/2) revealed distinct patterns in granulosa cells and leukocytes. Conclusions: Expression of the FMR1 gene during human folliculogenesis is probably a quantitative trait. That means, proper function of FMRP during folliculogenesis in granulosa cells depends on an optimal controlled transcript level because FMRP is part of these cells RISC controlling translation of many other granulosa cell transcripts. The FMR1 transcript level is not just depending on the number of CGG triplets in FMR1 exon1. An epigenetic control mechanism is indicated additionally by presence of distinct CpG methylation patterns in the CpG island of the FMR1 promoter domain including the epigenetically controlled FREE1/2 sequence domains. If this holds true, the high variation of the FMR1 transcript level found in blood cells of only POI/POF patients might be diagnostic for a functional drawback of FMRP in granulosa cells because these cells control the oocyte maturation process. fertility can be identified in at least twice as many cycles. In fact, if 20 tests are used, peak fertility could be identified in almost all cycles.

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