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Ectopic expression of CGG-repeats alters ovarian response to gonadotropins and leads to infertility in a murine FMR1 premutation model
- Source :
- Hum Mol Genet
- Publication Year :
- 2021
- Publisher :
- Oxford University Press (OUP), 2021.
-
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.
- Subjects :
- Infertility
congenital, hereditary, and neonatal diseases and abnormalities
media_common.quotation_subject
Ovary
Primary Ovarian Insufficiency
Biology
Ectopic Gene Expression
Andrology
Transcriptome
Fragile X Mental Retardation Protein
Mice
03 medical and health sciences
0302 clinical medicine
Lipid biosynthesis
Tremor
Genetics
medicine
Animals
Humans
Molecular Biology
Ovulation
Genetics (clinical)
030304 developmental biology
media_common
0303 health sciences
General Medicine
Oocyte
medicine.disease
FMR1
nervous system diseases
Disease Models, Animal
medicine.anatomical_structure
Fragile X Syndrome
Oocytes
Ataxia
Female
Ectopic expression
General Article
Peptides
Trinucleotide Repeat Expansion
Gonadotropins
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....9d361c73b1b9fbbb16a6029eb0b6e14e