Novel mutations in the TP63 gene are potentially associated with Müllerian duct anomalies

Wang, Xiaoyan; Zhang, Xiruo; Liu, Shan; Li, Guangyu; Cui, Linlin; Qin, Yingying; Chen, Zi‐Jiang

doi:10.1093/humrep/dew259

Cited by 9 publications

(6 citation statements)

References 25 publications

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“…Although we previously revealed the role of TP63 mutations in the 3′–UTR in human Müllerian duct anomalies ( 39 ), neither the patients with POI nor the mouse models in this study showed defects in the reproductive tract, which might be due to the differences in mutation sites/types and the expression of tissue-specific isoforms. There is also evidence that p63 functions in spermatogenesis in males.…”

Section: Discussioncontrasting

confidence: 65%

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis

Huang¹,

Zhao²,

Yang³

et al. 2023

Journal of Clinical Investigation

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The transcription factor p63 guards genome integrity in the female germline, and its mutations have been reported in patients with premature ovarian insufficiency (POI). However, the precise contribution of the TP63 gene to the pathogenesis of POI needs to be further determined. Here, in 1,030 Chinese patients with POI, we identified 6 heterozygous mutations of the TP63 gene that impaired the C-terminal transactivation-inhibitory domain (TID) of the TAp63α protein and resulted in tetramer formation and constitutive activation of the mutant proteins. The mutant proteins induced cell apoptosis by increasing the expression of apoptosis-inducing factors in vitro. We next introduced a premature stop codon and selectively deleted the TID of TAp63α in mice and observed rapid depletion of the p63 +/ Δ TID mouse oocytes through apoptosis after birth. Finally, to further verify the pathogenicity of the mutation p.R647C in the TID that was present in 3 patients, we generated p63 +/R647C mice and also found accelerated oocyte loss, but to a lesser degree than in the p63 +/ Δ TID mice. Together, these findings show that TID-related variants causing constitutive activation of TAp63α lead to POI by inducing oocyte apoptosis, which will facilitate the genetic diagnosis of POI in patients and provide a potential therapeutic target for extending female fertility.

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Section: Discussioncontrasting

confidence: 65%

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis

Huang¹,

Zhao²,

Yang³

et al. 2023

Journal of Clinical Investigation

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“…Congenital malformations of the Müllerian duct system are very likely multifactorial in etiology, resulting from polygenic and familial factors. Mutations in the TP63 gene are potentially associated with Müllerian duct anomalies [3]. Unicornuate uterus composes 2.4-13% of all Müllerian anomalies, and is found in approximately 0.1% of the general population [1].…”

Section: Discussionmentioning

confidence: 99%

Term pregnancy not requiring cerclage placement or tocolytic therapy in a patient with a unicornuate uterus and history of myomectomy

Biljic-Erski¹,

Vasiljevic²,

Rakic³

et al. 2019

Clin. Exp. Obstet. Gynecol.

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The authors present the case of a 28-year-old nulliparous woman, who successfully carried a term pregnancy in a unicornuate uterus with a solid non-communicating rudimentary horn, and a history of myomectomy, without cerclage placement or tocolytic therapy. The patient was admitted to the present clinic for uterine fibroids and menorrhagia. The patient underwent laparotomy, during which a myomectomy was performed. Twelve months after the surgery, the patient conceived spontaneously. Routine obstetric ultrasounds revealed normal intrauterine fetal development. Cerclage and tocolytic therapy were not indicated at any stage of the pregnancy. A live female neonate was delivered via cesarean section at 39 weeks' gestation.

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“…Tumor suppressor protein Incorrect epithelial differentiation of lower genital tract [26] SNPs associated with MD anomalies [27] TCF2 (HNF1ß) Homeodomain TF NA MRKH syndromeSevere genital malformations [28]…”

Section: Hoxa13mentioning

confidence: 99%

“…A genome-wide association study (GWAS) found that two single nucleotide polymorphisms (SNPs) in WNT9B were significantly associated with MRKH syndrome [ 17 ]. Sequencing also revealed SNPs in the TP63 gene among women with MD anomalies [ 27 ]. In HFG syndrome, there are defects in MD fusion and patterning.…”

Section: Endometrium Development and Biologymentioning

confidence: 99%

Modeling Endometrium Biology and Disease

Maenhoudt¹,

Moor²,

Vankelecom³

2022

JPM

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The endometrium, lining the uterine lumen, is highly essential for human reproduction. Its exceptional remodeling plasticity, including the transformation process to welcome and nest the embryo, is not well understood. Lack of representative and reliable study models allowing the molecular and cellular mechanisms underlying endometrium development and biology to be deciphered is an important hurdle to progress in the field. Recently, powerful organoid models have been developed that not only recapitulate endometrial biology such as the menstrual cycle, but also faithfully reproduce diseases of the endometrium such as endometriosis. Moreover, single-cell profiling endeavors of the endometrium in health and disease, and of derived organoids, start to provide deeper insight into cellular complexity and expression specificities, and in resulting tissue processes. This granular portrayal will not only help in understanding endometrium biology and disease, but also in pinning down the tissue’s stem cells, at present not yet conclusively defined. Here, we provide a general overview of endometrium development and biology, and the efforts of modeling both the healthy tissue, as well as its key diseased form of endometriosis. The future of modeling and deciphering this key tissue, hidden inside the womb, looks bright.

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Novel mutations in the TP63 gene are potentially associated with Müllerian duct anomalies

Cited by 9 publications

References 25 publications

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis

Term pregnancy not requiring cerclage placement or tocolytic therapy in a patient with a unicornuate uterus and history of myomectomy

Modeling Endometrium Biology and Disease

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