Ovarian Abnormalities in a Mouse Model of Fragile X Primary Ovarian Insufficiency

摘要: The X-linked FMR1 gene has an expansion-prone CGG·CCG-repeat in its 5′ untranslated region (UTR) (Kremer et al. 1991; Verkerk 1991). There are two pathological allele size classes seen the human population. Full-mutation (FM) alleles have >200 repeats and associated with silencing a developmental disorder known as fragile X syndrome. In contrast, 55 to 200 repeats, so-called premutation (PM) alleles, risk for neurodegenerative disorder, X– tremor ataxia syndrome (FXTAS) (Hagerman Hagerman 2001), form of ovarian dysfunction X–associated primary insufficiency (FXPOI) (Vianna-Morgante 1996; Murray 2000; Sherman 2000). FXPOI involves infertility, irregular menses, early menopause. This is accompanied by increased rate twinning 1999), elevated levels follicle-stimulating hormone (FSH), reduced anti-Mullerian (AMH), progesterone, inhibins A B (Murray 1999; Welt 2004; Gleicher 2010), similar what normal premenopause. It thought that accounts ~11.5% familial cases ~3.2% sporadic 1998; Marozzi Mallolas 2001; Bussani 2004). Even absence FXPOI, PM carriers group enter menopause on average five years earlier than do their siblings without (Sherman 2000). Because carrier frequency between 1:115 1:259 (Toledano-Alhadef 2008; Hantash 2011), understanding basis important because ramifications being extend beyond issue childbearing conditions postmenopausal years, such coronary heart disease osteoporosis. Because can result doubling age-related mortality (Snowdon 1989), this significant public health issue. The molecular brain pathology unknown. repeat expansion mutation responsible occurs outside open reading frame, amino acid sequence product, FMRP, not affected. Furthermore, FMRP much higher (although slightly below levels) FM who show symptoms. This, together fact ectopic expression RNA containing long CGG-repeat tract deleterious variety cells causes neurodegeneration both flies mice (Handa 2003; Jin Arocena 2005; Hashem 2009), led suggestion it pathology. By analogy myotonic dystrophy type 1 2, other diseases, been suggested symptoms could arise from sequestering key protein factors CGG-RNA (Jin 2007; Sofola Sellier 2010). However, despite large body work published area FXTAS, mechanism remains subject debate. situation even less clear, relatively few studies having published, all which focused epidemiology clinical description condition. Not only no mechanistic done, but tissue culture or mouse model may be useful understand thus far described. Previously, we described generation targeted insertion ~130 CGG murine Fmr1 (Entezam 2007); offspring these had mRNA like carriers, were lower mice. These also showed clear neuropathological changes many regions those reported postmortem samples humans FXTAS (Greco 2002; Willemsen 2003). detailed study yet ovaries animals. We describe here results our characterization at cellular level. We initial primordial follicle pool more rapid depletion follicular reserve wild-type (WT) animals differences WT reflect underlying pathology, including smaller number granulosa (GCs) per follicle, coronal abnormalities, atresia. Oocytes abnormal distribution high ubiquitination. Our data suggest FX generated good able provide insights into carriers.