XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. Most cases are unexplained but thought to be autosomal recessive. We elucidated the genetic basis of XX-GD in a highly consanguineous Palestinian family by using homozygosity mapping and candidate-gene and whole-exome sequencing. Affected females were homozygous for a 3 bp deletion (NM-016556.2, c.600-602del) in the PSMC3IP gene, leading to deletion of a glutamic acid residue (p.Glu201del) in the highly conserved C-terminal acidic domain. Proteasome 26S subunit, ATPase, 3-Interacting Protein (PSMC3IP)/Tat Binding Protein Interacting Protein (TBPIP) is a nuclear, tissue-specific protein with multiple functions. It is critical for meiotic recombination as indicated by the known role of its yeast ortholog, Hop2. Through the C terminus (not present in yeast), PSMC3IP also coactivates ligand-driven transcription mediated by estrogen, androgen, glucocorticoid, progesterone, and thyroid nuclear receptors. In cell lines, the p.Glu201del mutation abolished PSMC3IP activation of estrogen-driven transcription. Impaired estrogenic signaling can lead to ovarian dysgenesis both by affecting the size of the follicular pool created during fetal development and by failing to counteract follicular atresia during puberty. PSMC3IP joins previous genes known to be mutated in XX-GD, the FSH receptor, and BMP15, highlighting the importance of hormonal signaling in ovarian development and maintenance and suggesting a common pathway perturbed in isolated XX-GD. By analogy to other XX-GD genes, PSMC3IP is also a candidate gene for premature ovarian failure, and its role in folliculogenesis should be further investigated.
Bibliographical noteFunding Information:
This study was supported by the Legacy Heritage Biomedical Program of the Israel Science Foundation (grant 1531/2009 to D.Z.), the Chief Scientist Office of the Ministry of Health, Israel (grant 3-00000-6245 to E.L.L) and a European Union Marie Curie International Reintegration grant (PIRG05-GA-2009-248639 to L.C.). We thank Mira Korner (The Center for Genomic Technologies, The Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem Israel) for performing massively parallel sequencing, Alberto Gabizon (Institute of Oncology, Shaare Zedek Medical Center, Jerusalem, Israel) for the kind gift of the IGROV1 cell line, Mary-Claire King and Sarah Pierce (Department of Genome Sciences, University of Washington, Seattle, WA), and Martin Kupiec (Department of Molecular Biology and Biotechnology, Tel Aviv University, Tel Aviv, Israel) for helpful discussions.