|
General Comment |
NCBI Summary:
This gene encodes a protein that functions in meiotic recombination. It is a subunit of the PSMC3IP/MND1 complex, which interacts with PSMC3/TBP1 to stimulate DMC1- and RAD51-mediated strand exchange during meiosis. The protein encoded by this gene can also co-activate ligand-driven transcription mediated by estrogen, androgen, glucocorticoid, progesterone, and thyroid nuclear receptors. Mutations in this gene cause XX female gonadal dysgenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2011]
|
|
Comment |
Human Ovarian Cancer Stroma Contains Luteinized Theca Cells Harboring Tumor Suppressor Gene GT198 Mutations. Peng M 2013 et al.
Ovarian cancer is a highly lethal gynecological cancer and its causes remain to be understood. Using a recently identified tumor suppressor gene GT198 (PSMC3IP) as unique marker, we search for the identity of GT198 mutant cells in ovarian cancer. GT198 has germline mutations in familial and early-onset breast and ovarian cancers and recurrent somatic mutations in sporadic fallopian tube cancers. GT198 protein has been shown as a steroid hormone receptor coregulator and also as a crucial factor in DNA repair. In this study, using GT198 as a marker for microdissection, we find that ovarian tumor stromal cells harboring GT198 mutations are present in various types of ovarian cancer including high- and low-grade serous, endometrioid, mucinous, clear cell, granulosa cell carcinomas, and in precursor lesions such as inclusion cysts. The mutant stromal cells consist of a luteinized theca cell lineage at various differentiation stages including CD133+, CD44+, CD34+ cells; although the vast majority of them are differentiated overexpressing steroidogenic enzyme CYP17, a theca cell-specific marker. In addition, wild type GT198 suppresses whereas mutant GT198 protein stimulates CYP17 expression. The chromatin-bound GT198 on the human CYP17 promoter is decreased by overexpressing mutant GT198 protein, implicating the loss of wild type suppression in mutant cells. Together, our results suggest that GT198 mutant luteinized theca cells overexpressing CYP17 are common in ovarian cancer stroma. Since first-hit cancer gene mutations would specifically mark cancer-inducing cells, the identification of mutant luteinized theca cells may add a crucial evidence in understanding the cause of human ovarian cancer.
/////////////////////////
|
|
Mutations |
2 mutations
Species: human
Mutation name:
type: naturally occurring
fertility: infertile - ovarian defect
Comment: XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription. Zangen D et al. (2011) 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.//////////////////
Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: The Hop2 protein has a direct role in promoting interhomolog interactions during mouse meiosis. Petukhova GV et al. (2004) The S. cerevisiae Hop2 protein and its fission yeast homolog Meu13 are required for proper homologous chromosome pairing and recombination during meiosis. The mechanism of this requirement is, however, not understood. The previous studies in Saccharomyces suggested that Hop2 is a guardian of meiotic chromosome synapsis with the ability to prevent or resolve deleterious associations between nonhomologous chromosomes. We have generated a Hop2 knockout mouse that shows profound meiotic defects with a distinct and novel phenotype. Hop2(-/-) spermatocytes arrest at the stage of pachytene-like chromosome condensation. Axial elements are fully developed, but synapsis of any kind is very limited. Immunofluorescence analysis of meiotic chromosome spreads indicates that while meiotic double-stranded breaks are formed and processed in the Hop2 knockout, they fail to be repaired. In aggregate, the Hop2 phenotype is consistent with a direct role for the mouse Hop2 protein in promoting homologous chromosome synapsis.//////////////////
|