A novel TP63 variant in a patient with ankyloblepharon-ectodermal defect–cleft lip/palate syndrome and Rapp–Hodgkin syndrome-like ectodermal dysplasia

Hori, Asuka; Migita, Ohsuke; Isogawa, Nobutaka; Takada, Fumio; Hata, Kenichiro

doi:10.1038/s41439-022-00186-w

Cited by 2 publications

(1 citation statement)

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“…TP63 is indispensable for embryonic craniofacial, skin, and limb development [ 26 ]. Some human diseases, such as limb malformations, ectodermal dysplasia, craniofacial anomalies, and isolated POI, have been reported to be related to TP63 [ 27 ]. Different studies have found that TP63 missense or truncation mutations cause POI [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

TP63 truncating mutation causes increased cell apoptosis and premature ovarian insufficiency by enhanced transcriptional activation of CLCA2

Fan,

Chen,

Chu

et al. 2024

J Ovarian Res

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Background Premature ovarian insufficiency (POI) is a severe disorder leading to female infertility. Genetic mutations are important factors causing POI. TP63-truncating mutation has been reported to cause POI by increasing germ cell apoptosis, however what factors mediate this apoptosis remains unclear. Methods Ninety-three patients with POI were recruited from Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Whole-exome sequencing (WES) was performed for each patient. Sanger sequencing was used to confirm potential causative genetic variants. A minigene assay was performed to determine splicing effects of TP63 variants. A TP63-truncating plasmid was constructed. Real-time quantitative PCR, western blot analyses, dual luciferase reporter assays, immunofluorescence staining, and cell apoptosis assays were used to study the underlying mechanism of a TP63-truncating mutation causing POI. Results By WES of 93 sporadic patients with POI, we found a 14-bp deletion covering the splice site in the TP63 gene. A minigene assay demonstrated that the 14-bp deletion variant led to exon 13 skipping during TP63 mRNA splicing, resulting in the generation of a truncated TP63 protein (TP63-mut). Overexpression of TP63-mut accelerated cell apoptosis. Mechanistically, the TP63-mut protein could bind to the promoter region of CLCA2 and activate the transcription of CLCA2 several times compared to that of the TP63 wild-type protein. Silencing CLCA2 using a specific small interfering RNA (siRNA) or inhibiting the Ataxia Telangiectasia Mutated (ATM) pathway using the KU55933 inhibitor attenuated cell apoptosis caused by TP63-mut protein expression. Conclusion Our findings revealed a crucial role for CLCA2 in mediating apoptosis in POI pathogenesis, and suggested that CLCA2 is a potential therapeutic target for POI.

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Section: Introductionmentioning

confidence: 99%