Abstract
The FMR1 gene contains a polymorphic CGG trinucleotide sequence within its 5′ untranslated region. More than 200 CGG repeats (termed a full mutation) underlie the severe neurodevelopmental condition fragile X syndrome, while repeat lengths that range between 55 and 200 (termed a premutation) result in the conditions fragile X-associated tremor/ataxia syndrome and fragile X-associated premature ovarian insufficiency (FXPOI). Premutations in FMR1 are the most common monogenic cause of premature ovarian insufficiency and are routinely tested for clinically; however, the mechanisms that contribute to the pathology are still largely unclear. As studies in this field move towards unravelling the molecular mechanisms involved in FXPOI aetiology, we review the evidence surrounding the two main theories which describe an RNA toxic gain-of-function mechanism, resulting in the loss of function of RNA-binding proteins, or a protein-based mechanism, where repeat-associated non-AUG translation leads to the formation of an abnormal polyglycine containing protein, called FMRpolyG.
Highlights
Fragile X-associated premature ovarian insufficiency (FXPOI) is among a family of disorders caused by the expansion of a CGG trinucleotide repeat sequence located in the 5’ untranslated region (UTR) of the FMR1 gene on the X chromosome
Much of the research into the molecular mechanisms underlying the pathology of FMR1-associated conditions has focussed on the neurological aspects: the aim of this review is to critically appraise putative mechanisms underlying the pathogenesis of fragile X-associated premature ovarian insufficiency (FXPOI), the evidence investigating the RNA gain-of-function hypothesis and the contribution of repeat-associated non-AUG (RAN) translation, drawing on parallels in fragile X-associated tremor/ataxia syndrome (FXTAS) and advances made in that disease
The authors describe a significant negative linear correlation between granulosa cell FMR1 expression and the number of oocytes retrieved after ovarian stimulation for preimplantation genetic diagnosis, with the most obvious effects observed in women carrying mid-range (80-120) repeat lengths. While these data are only correlative, these findings suggest that FMR1 mRNA accumulation in granulosa cells may be an important cause of follicle dysfunction and loss
Summary
The molecular mechanisms that underlie fragile X-associated premature ovarian insufficiency: is it RNA or protein based?. Citation for published version: Rosario, R & Anderson, RA 2020, 'The molecular mechanisms that underlie fragile X-associated premature ovarian insufficiency: is it RNA or protein based?', Molecular Human Reproduction. Roseanne Rosario and Richard Anderson MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom EH16 4TJ.
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