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| Status |
Public on Jun 11, 2024 |
| Title |
Deleterious variants in RNF111 impair female fertility and induce premature ovarian insufficiency in humans and mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Premature ovarian insufficiency (POI) is a heterogeneous female disorder characterized by the loss of ovarian function before the age of 40. It represents a significant detriment to female fertility. However, the known POI-causative genes currently account for only a fraction of cases. To elucidate the genetic factors underlying POI, we conducted whole-exome sequencing on a family with three fertile POI patients and identified a deleterious missense variant in RNF111. In a subsequent replication study involving 1030 POI patients, this variant was not only confirmed but also accompanied by the discovery of three additional predicted deleterious RNF111 variants. These variants collectively account for eight cases, representing 0.78% of the study cohort. A further study involving 500 patients with diminished ovarian reserves also identified two additional RNF111 variants. Notably, RNF111 encodes an E3-ubiquitin ligase with a regulatory role in the TGF-β/BMP signaling pathway. Our analysis revealed that RNF111/RNF111 is predominantly expressed in the oocytes of mice, monkeys, and humans. To further investigate the functional implications of RNF111 variants, we generated two mouse models: one with a heterozygous missense mutation (Rnf111+/M) and another with a heterozygous null mutation (Rnf111+/−). Both mouse models exhibited impaired female fertility, characterized by reduced litter sizes and small ovarian reserve. Additionally, RNA-seq and quantitative proteomics analysis unveiled that Rnf111 haploinsufficiency led to dysregulation in female gonad development and negative regulation of the BMP signaling pathway within mouse ovaries. In conclusion, our findings strongly suggest that monoallelic deleterious variants in RNF111 can impair female fertility and induce POI in both humans and mice.
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| Overall design |
To investigate the functional implication of monoallelic deleterious variants in RNF111 to premature ovarian insufficiency, we generated two mouse models using CRISPR-Cas9. To further investigate the functional alterations within the mutant mouse ovaries, We then performed bulk RNA-seq analyses on ovaries from wild-type and Rnf111+/- mice.
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| Web link |
https://doi.org/10.1007/s11427-024-2606-6
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| Contributor(s) |
Song C, Qin Y, Li Y, Yang B, Guo T, Ma W, Xu D, Xu K, Fu F, Jin L, Wu Y, Tang S, Chen X, Zhang F |
| Citation(s) |
38874713 |
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| Submission date |
Jan 09, 2024 |
| Last update date |
Sep 10, 2024 |
| Contact name |
Chengcheng Song |
| E-mail(s) |
song-chengcheng@outlook.com
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| Phone |
13127533553
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| Organization name |
Fudan University
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| Street address |
220 Handan Rd.
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| City |
Shanghai |
| State/province |
Shanghai |
| ZIP/Postal code |
200438 |
| Country |
China |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| GSM8007880 |
Ovary, 3 months old, estrus, mouse het_KO1 |
| GSM8007881 |
Ovary, 3 months old, estrus, mouse het_KO2 |
| GSM8007882 |
Ovary, 3 months old, estrus, mouse het_KO3 |
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| Relations |
| BioProject |
PRJNA1062707 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE252791_raw_counts.txt.gz |
337.3 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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