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

Abstract

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.

Genetics of primary ovarian insufficiency

“…All the identified variants were not found in 316 matched controls (160). Another gene required for homologous recombination, PSMC3IP (MIM *608665) has been found to harbor variations causative of POI (35).…”

“…The analysis of a few cohorts of 46,XX POI patients by means of high throughput techniques, such as comparative genomic hybridization array (array-CGH) and SNP array, has led to the identification of CNVs affecting several X-linked and autosomal loci with a possible role in female fertility (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Similarly, the recent application of whole-exome sequencing (WES) to a few POI multigenerational familial cases has succeeded in revealing rare single nucleotide variants affecting genes implicated in ovarian function (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). As already reported in other complex diseases characterized by a great genetic heterogeneity, it is likely that patients with POI may harbor multiple genetic variants.…”

GT198 Splice Variants Display Dominant-Negative Activities and Are Induced by Inactivating Mutations

“…32 A germline deletion in GT198 has been identified in a diseased family of ovarian dysgenesis, supporting its critical role in ovarian development. 33 In an accompanying study of familial breast and ovarian cancer (Peng et al, in this issue), we have identified GT198 germline and somatic mutations including splicing mutations. Although GT198 splice variant mRNA are evident in the National Center for Biotechnology Information (NCBI) databases, their regulation has not been described.…”

Human Ovarian Cancer Stroma Contains Luteinized Theca Cells Harboring Tumor Suppressor Gene GT198 Mutations

“…GT198 has also been extensively shown to regulate homologous recombination in DNA repair (21,22) and to stimulate Rad51-mediated DNA strand exchange (23). A homozygous germ line deletion mutation in GT198 is identified in familial ovarian dysgenesis disease (24). We have recently identified GT198 germ line mutations in familial and early onset breast and ovarian cancers (25) and prevalent GT198 somatic mutations in sporadic fallopian tube cancers (26).…”