We evaluated an adopted 29-year-old Chinese woman with POI and identified two biallelic mutations, c.597 + 1G > T and c.268G > C, in the PSMC3IP gene. The two mutations carried by the patient were inherited respectively from her biological mother and father. PSMC3IP has previously been linked to hereditary breast and ovarian cancer, as well as causing autosomal recessive POI [8, 10, 11]. PSMC3IP defects can disrupt estrogen-driven transcription activation of PSMC3IP. Impaired estrogenic signaling can result in ovarian dysgenesis by interfering the follicular pool and against counteracting follicular atresia [8, 12].
The PSMC3IP gene is located at 17q21.2, consist of 217 amino acids in its monomer, encoding a nuclear, tissue-specific protein with multiple functions, including a role in meiotic recombination and acting as a coactivator of ligand-dependent transcription mediated by nuclear hormone receptors, which is conserved in evolution [13, 14]. Previous studies proved that in the PSMC3IP knockout model of mice, the ovarian volume is reduced and the germ cells are missing[15, 16]. PSMC3IP is a DNA-binding protein dime, characterized by the presence of three domains including a leucine zipper domain, a DNA-binding domain, and a RAD51/DMC1 interaction domain [17]. The c.268G > C mutation occurs within the highly conserved leucine zipper domains(Fig. 4c). In vitro experiments showed that a defect of the leucine zipper eliminated the dimerization of PSMC3IP [13]. The c.268G > C mutation was detected in the proband’s mother and sister with normal ovarian function. The splicing mutation c.597 + 1G > T is predicted to alter the splice donor site so that most likely to interfere with splicing. However, the exact effects of splice site mutations on mRNA cleavage are not clear and need to be investigated further.
To date, only four POI families with PSMC3IP mutations have been described worldwide, including one reported in this paper(Table 1). A total of six pathogenic PSMC3IP mutations have been identified, comprising three frameshift mutations, one nonsense mutation, one missense mutation, and a splicing mutation. In 2011, Zangen et al. [8] first identified a homozygous 3 bp in-frame deletion in the exon 8 of PSMC3IP gene in a large consanguineous Arab Palestinian pedigree with XX-female gonadal dysgenesis, leading to the deletion of glu201. Also, in a consanguineous Yemeni family of a brother with azoospermia and four sisters with ovarian dysgenesis, Abdulmoein et al. [17] identified a homozygous stop mutation (c.489C > G, p.Tyr163Ter) in PSMC3IP, suggesting an important role of PSMC3IP in the development of male and female germ cells. In our study, the proband’s father and older brother carried the heterozygous splice site mutation c.597 + 1G > T, but none of them showed spermatogenesis dysfunction. Recently, two compound heterozygous mutations of PSMC3IP (c.430_431insGA, p.L144*; c.496_497delCT, p.R166Afs) were found in a 28-year-old French female who presented with POI [18]. Since the limited number of cases of PSMC3IP mutations associated with POI, we are not able to make a clear correlation between this genotype and phenotype.
Table 1
Family | Age at diagnosis | Ethnic origin | CS | karyotype | Nucleotide change | Amino acid change | Status | Reference |
1 | 21 | Palestinian | Yes | 46,XX | c.[600_602del] | p.Glu201del | ho | Zangen et al., (2011) |
2 | 28 | French | No | 46,XX | c.[496_497delCT]+[430_431insGA] | p.[R166Afs]+[L144X] | He | Xiang et al.,(2018) |
3 | 27 | Yemen | Yes | 46,XX | c.[489 C > G] | p.[Tyr163Ter] | ho | Al-Agha et al.,(2018) |
4 | 29 | Chinese | No | 46,XX | c.[597 + 1G > T]+[268G > C] | P.[splicing]+[p.D90H] | He | This study |
CS, consanguineous; he, heterozygous; and ho, homozygous. |