Ectopic expression of CGG-repeats alters ovarian response to gonadotropins and leads to infertility in a murine FMR1 premutation model

Author:

Shelly Katharine E1,Candelaria Nicholes R2,Li Ziyi3,Allen Emily G4,Jin Peng4,Nelson David L1

Affiliation:

1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA

2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA

3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

4. Department of Human Genetics, Emory University, Atlanta, GA 30322, USA

Abstract

Abstract 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.

Funder

National Institutes of Health

National Institute of General Medical Science’s

National Institute of Neurological Disorders and Stroke

Eunice Kennedy Shriver National Institute of Child Health & Human Development

Publisher

Oxford University Press (OUP)

Subject

Genetics(clinical),Genetics,Molecular Biology,General Medicine

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