Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI)

• Type of Material: Article
• Authors: Stephanie Sherman, Emory University; Eliza C Curnow, University of Washington; Charles Easley, Emory University; Peng Jin, Emory University; Renate K Hukema, Erasmus University Medical Center; Maria Isabel Tejada, Hospital Universitario Cruces; Rob Willemsen, Erasmus University Medical Center; Karen Usdin, National Institutes of Health
• Language: English
• Date: 2014-08-13
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Sherman et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://dx.doi.org/10.1186/1866-1955-6-26
• Title of Journal or Parent Work: Journal of Neurodevelopmental Disorders
• ISSN: 1866-1947
• Volume: 6
• Issue: 1
• Start Page: 26
• End Page: 26
• Grant/Funding Information: Emory's Genetics Discovery Fund (SLS); National Institute of Child Health and Development and National Institute of Mental Health at the National Institutes of Health R21HD071876 for support of NHP studies (ECC); The Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (KU); The National Fragile X Foundation (RKH, RW)
• Keywords: Fertility; Repeat expansion disorder; Primary ovarian insufficiency; Fragile X syndrome; Premature ovarian failure; CGG repeat

Abstract

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.