XX Ovarian Dysgenesis Is Caused by a PSMC3IP/HOP2 Mutation that Abolishes Coactivation of Estrogen-Driven Transcription

摘要: 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 result streak gonads. Most cases are unexplained but thought to be autosomal recessive. We elucidated the genetic basis XX-GD in highly consanguineous Palestinian family using homozygosity mapping candidate-gene whole-exome sequencing. Affected females were homozygous for 3 bp deletion (NM_016556.2, c.600_602del) PSMC3IP gene, leading glutamic acid residue (p.Glu201del) conserved C-terminal acidic domain. Proteasome 26S subunit, ATPase, 3-Interacting Protein (PSMC3IP)/Tat Binding Interacting (TBPIP) nuclear, tissue-specific protein with multiple functions. It critical meiotic recombination indicated known role its yeast ortholog, Hop2. Through C terminus (not present yeast), also coactivates ligand-driven transcription mediated estrogen, androgen, glucocorticoid, progesterone, thyroid nuclear receptors. In cell lines, p.Glu201del mutation abolished activation estrogen-driven transcription. Impaired estrogenic signaling can lead ovarian both affecting size follicular pool created during fetal development failing counteract atresia puberty. joins previous genes mutated XX-GD, FSH receptor, BMP15, highlighting importance hormonal maintenance suggesting common pathway perturbed isolated XX-GD. By analogy other genes, candidate gene premature failure, folliculogenesis should further investigated.