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Journal of Neurodevelopmental Disorders

, 6:26

FMR1 premutation


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.

KeywordsPrimary ovarian insufficiency Premature ovarian failure Fragile X syndrome Fertility Repeat expansion disorder CGG repeat AbbreviationsFXPOIfragile X-associated primary ovarian insufficiency

FXTASfragile X-associated tremor-ataxia syndrome

GCgranulosa cell

GSCgerm-line stem cell

iPSCinduced pluripotent stem cell





NHPnon-human primate


POFpremature ovarian failure

POIprimary ovarian insufficiency

RANrepeat-associated non-ATG

UTRuntranslated region

XCIX-chromosome inactivation

WTwild type

YACyeast artificial chromosome.

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Autor: Stephanie L Sherman - Eliza C Curnow - Charles A Easley - Peng Jin - Renate K Hukema - Maria Isabel Tejada - Rob Wille


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