ArticleHuman mutation2022
Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency.
Article in Human mutation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 31 citations in OpenAlex.
- Article
- Identification of novel tumor protein 63 variant associated with split-hand/foot malformation and tooth agenesis.Frontiers in medicine · 2026Article
- A TAp63alpha truncating variant associated with primary ovarian insufficiency lowers the cellular apoptotic rate.Journal of ovarian research · 2025Article
- p63: A Master Regulator at the Crossroads Between Development, Senescence, Aging, and Cancer.Cells · 2025Review
- Genetics of ovulatory dysfunction and infertility: a scoping review and gene ontology analysis.Frontiers in endocrinology · 2025Article
- Advances in the genetic etiology of female infertility.Journal of assisted reproduction and genetics · 2024Review
- Premature ovarian insufficiency.Nature reviews. Disease primers · 2024Review
- TP63 truncating mutation causes increased cell apoptosis and premature ovarian insufficiency by enhanced transcriptional activation of CLCA2.Journal of ovarian research · 2024Article
- A Human HomozygousGenes · 2024Article
- Improving diagnostic precision in primary ovarian insufficiency using comprehensive genetic and autoantibody testing.Human reproduction (Oxford, England) · 2024Article
- Primary ovarian insufficiency: update on clinical and genetic findings.Frontiers in endocrinology · 2024Review
- Heterozygous TP63 pathogenic variants in isolated primary ovarian insufficiency.Journal of assisted reproduction and genetics · 2023Article
- TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.The Journal of clinical investigation · 2023Article
- Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency.Human mutation · 2022Article
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Premature ovarian insufficiency (POI) is a leading form of female infertility, characterised by menstrual disturbance and elevated follicle-stimulating hormone before age 40. It is highly heterogeneous with variants in over 80 genes potentially causative, but the majority of cases having no known cause. One gene implicated in POI pathology is TP63. TP63 encodes multiple p63 isoforms, one of which has been shown to have a role in the surveillance of genetic quality in oocytes. TP63 C-terminal truncation variants and N-terminal duplication have been described in association with POI, however, functional validation has been lacking. Here we identify three novel TP63 missense variants in women with nonsyndromic POI, including one in the N-terminal activation domain, one in the C-terminal inhibition domain, and one affecting a unique and poorly understood p63 isoform, TA*p63. Via blue-native page and luciferase reporter assays we demonstrate that two of these variants disrupt p63 dimerization, leading to constitutively active p63 tetramer that significantly increases the transcription of downstream targets. This is the first evidence that TP63 missense variants can cause isolated POI and provides mechanistic insight that TP63 variants cause POI due to constitutive p63 activation and accelerated oocyte loss in the absence of DNA damage.
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