Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Hum Mol Genet. 2021 May 29;30(10):923-938. doi: 10.1093/hmg/ddab083.
Women heterozygous for an expansion of CGG repeats in the 5'UTR of FMR1 risk developing fragile X-associated primary ovarian insufficiency (FXPOI) and/or tremor and ataxia syndrome (FXTAS). We show that expanded CGGs, independent of FMR1, are sufficient to drive ovarian insufficiency and that expression of CGG-containing mRNAs alone or in conjunction with a polyglycine-containing peptide translated from these RNAs contribute to dysfunction. Heterozygous females from two mouse lines expressing either CGG RNA-only (RNA-only) or CGG RNA and the polyglycine product FMRpolyG (FMRpolyG+RNA) were used to assess ovarian function in aging animals. The expression of FMRpolyG+RNA led to early cessation of breeding, ovulation and transcriptomic changes affecting cholesterol and steroid hormone biosynthesis. Females expressing CGG RNA-only did not exhibit decreased progeny during natural breeding, but their ovarian transcriptomes were enriched for alterations in cholesterol and lipid biosynthesis. The enrichment of CGG RNA-only ovaries for differentially expressed genes related to cholesterol processing provided a link to the ovarian cysts observed in both CGG-expressing lines. Early changes in transcriptome profiles led us to measure ovarian function in prepubertal females that revealed deficiencies in ovulatory responses to gonadotropins. These include impairments in cumulus expansion and resumption of oocyte meiosis, as well as reduced ovulated oocyte number. Cumulatively, we demonstrated the sufficiency of ectopically expressed CGG repeats to lead to ovarian insufficiency and that co-expression of CGG-RNA and FMRpolyG lead to premature cessation of breeding. However, the expression of CGG RNA-alone was sufficient to lead to ovarian dysfunction by impairing responses to hormonal stimulation.
女性携带 FMR1 5'UTR 中 CGG 重复序列扩张的杂合子，有患脆性 X 相关原发性卵巢功能不全 (FXPOI) 和/或震颤共济失调综合征 (FXTAS) 的风险。我们表明，独立于 FMR1 的扩展 CGG 足以导致卵巢功能不全，并且仅表达含有 CGG 的 mRNA 或与从这些 RNA 翻译的多聚甘氨酸肽一起表达会导致功能障碍。来自表达仅 CGG RNA（RNA-only）或 CGG RNA 和多聚甘氨酸产物 FMRpolyG（FMRpolyG+RNA）的两条小鼠品系的杂合雌性用于评估老年动物的卵巢功能。FMRpolyG+RNA 的表达导致繁殖、排卵和影响胆固醇和类固醇激素生物合成的转录组变化的早期停止。表达 CGG RNA-only 的雌性在自然繁殖期间不会减少后代，但它们的卵巢转录组富含胆固醇和脂质生物合成的改变。仅 CGG RNA 卵巢中与胆固醇处理相关的差异表达基因的富集为在两条 CGG 表达系中观察到的卵巢囊肿提供了联系。转录组谱的早期变化促使我们在青春期前雌性中测量卵巢功能，发现促性腺激素对排卵反应存在缺陷。这些包括卵丘扩展和卵母细胞减数分裂恢复的损伤，以及排出的卵母细胞数量减少。总而言之，我们证明了异位表达的 CGG 重复足以导致卵巢功能不全，并且 CGG-RNA 和 FMRpolyG 的共表达导致繁殖的过早停止。然而，仅表达 CGG RNA 足以通过损害对激素刺激的反应导致卵巢功能障碍。
