A number sign (#) is used with this entry because of evidence that premature ovarian failure-21 (POF21) is caused by heterozygous mutation in the TP63 gene (603273) on chromosome 3q28.

Premature ovarian failure-21 (POF21) is characterized by female infertility due to primary or secondary amenorrhea. Ovaries are small, atrophic, or nonvisualized on ultrasound (Tucker et al., 2019; Tucker et al., 2022).

For a general phenotypic description and a discussion of genetic heterogeneity of POF, see POF1 (311360).

Tucker et al. (2019) reported 2 unrelated women with premature ovarian insufficiency and mutation in the TP63 gene. The first patient (patient 8) was diagnosed at age 16 years with primary amenorrhea and incomplete puberty. The second patient (patient FRA125) presented with primary amenorrhea and had delayed puberty. Both patients showed elevated serum follicle-stimulating hormone (FSH; see 136530) and low anti-mullerian hormone (AMH; 600957) levels. Skeletal analysis showed delayed bone age in patient 8 and osteoporosis in patient FRA125. Neither patient had syndromic malformations.

Tucker et al. (2022) reported 4 women from 3 families with POF and mutation in the TP63 gene. Secondary amenorrhea was present in 3 of the patients, and 1 had primary amenorrhea and delayed puberty. Patient 1 was a 24-year-old woman who had menarche at age 13 with a second period at age 15, after which she took oral contraceptive pills (OCP), and experienced secondary amenorrhea at age 24 after stopping OCP. She had atrophic ovaries ('streak gonads') and a small uterus by ultrasound, and exhibited mild hirsutism, including facial hair. Patient 1 had a similarly affected paternal aunt, who showed a single atrophic right ovary and small uterus on ultrasound; exploratory endoscopy did not visualize any ovaries. She also had facial hirsutism. Family history revealed 4 additional paternal aunts with infertility and atrophic ovaries, and there were other family members with infertility but no other clinical information. Patient 2 was a 27-year-old woman who underwent menarche at age 13 and had regular periods from 13 to 15 years of age; she took OCP from 17 to 27 years of age, at which time she had secondary amenorrhea upon stopping OCP. Ultrasound examination revealed atrophic ovaries devoid of follicles and a small uterus. Patient 3 was a 21-year-old woman with delayed puberty and primary amenorrhea; no ovaries were visualized on ultrasound and she had an atrophic uterus and short vagina, as well as clitoral hypertrophy. Hormonal analysis in the 3 probands showed elevated FSH and LH (see 152790), and low estradiol and AMH levels.

From a cohort of 1,030 Chinese women diagnosed with premature ovarian insufficiency, Huang et al. (2023) identified 8 unrelated Chinese women (patients 4 to 11) with pathogenic mutations in the TP63 gene. Patients 4 to 7 had primary amenorrhea, and patients 8 to 11 experienced secondary amenorrhea before 30 years of age. Ovaries were small or nonvisualized. Hormone analysis showed elevated serum FSH and low estradiol levels.

The transmission pattern of POF21 in the families reported by Tucker et al. (2022) was consistent with autosomal dominant inheritance.

In a cohort of 13 patients with POF, Tucker et al. (2019) performed whole-exome sequencing (WES) and identified a 16-year-old girl with primary amenorrhea (patient 8) who was heterozygous for a de novo nonsense mutation in the last exon (exon 14) of the TP63 gene (R594X; 603273.0030). Sanger sequencing of exon 14 of TP63 in a cohort of 107 patients with POF revealed another patient with primary amenorrhea (patient FRA125) who was heterozygous for a different nonsense mutation (W598X; 603273.0031).

As part of a larger study using WES to investigate the genetic basis of POF, Tucker et al. (2022) identified 3 unrelated patients with rare heterozygous missense mutations in the TP63 gene: patient 1 and her affected aunt had an R97P substitution (603273.0032), patient 2 had an R647C substitution (603273.0033), and patient 3 had a Y18C substitution. The R97P and R647C substitutions were shown to disrupt TP63 dimerization, causing an open active tetramer conformation with a significant increase in transcriptional activity, whereas the third variant, Y18C, had no detectable impact on conformation or transcriptional activity. The authors suggested that POF-related variants cause constitutive activation of the oocyte-specific TAp63-alpha isoform, increasing expression of downstream targets that can initiate the apoptotic pathway in oocytes.

Huang et al. (2023) analyzed WES data from a cohort of 1,030 Chinese women diagnosed with premature ovarian insufficiency, and identified 8 unrelated Chinese women with heterozygous mutations in the TP63 gene, including 3 (patients 8, 9, and 10) with secondary amenorrhea and the previously reported R647C substitution, and 1 (patient 5) with primary amenorrhea and the R594X mutation. All but 1 of the mutations were in exon 14 of TP63; patient 4, who had primary amenorrhea, was heterozygous for a 1-bp deletion in exon 13 (603273.0034). The mutations were confirmed by Sanger sequencing and were either not found or were present at low minor allele frequency in the ExAC and/or gnomAD databases. Functional analysis suggested that these variants, which affect the C-terminal transactivation-inhibitory domain (TID), disrupt the inactive TP63 conformation, generating constitutively active TAp63-alpha that increases expression of target genes and induces apoptosis, thus causing exhaustion of oocytes that results in premature ovarian failure.

Huang et al. (2023) generated mice with a stop codon prior to the TID in exon 14 of the p63 gene, selectively altering the oocyte-specific p63-alpha isoform. Heterozygous mutant females were infertile, whereas mutant males were fertile. Ovary size in the mutant female mice was markedly reduced, and the number of follicles was substantially reduced at postnatal day 1 (P1), with follicles completely absent by P21. Oocyte numbers were reduced to approximately 40% of those of wildtype mice, and had completely disappeared by P10. The mutant females showed elevated FSH and decreased estradiol levels. The authors suggested that expression of mutant p63 lacking the TID resulted in rapid depletion of oocytes and loss of fertility, similar to the human POF phenotype. Immunofluorescence staining of P1 ovarian sections showed a significant increase in cleaved-PARP1 (173870)-positive oocytes in mutant ovaries compared to wildtype. Increased expression of Bax (600040), Puma (BBC3; 605854), and Noxa (PMAIP1; 604959) was observed, suggesting that deleting the TID of the p63 protein was sufficient to induce uncontrolled apoptosis of oocytes in primordial follicles without exogenous damage. In vitro analysis in SAOS-2 cells confirmed that activated p63 lacking the TID triggers downstream proapoptotic pathways, causing oocyte exhaustion and infertility.