Alternative titles; symbols
HGNC Approved Gene Symbol: PSMC3IP
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38) : 17:42,572,310-42,577,831 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | Ovarian dysgenesis 3 | 614324 | Autosomal recessive | 3 |
The PSMC3IP gene encodes a nuclear, tissue-specific protein with multiple functions, including a role in meiotic recombination and as a coactivator of ligand-dependent transcription mediated by nuclear hormone receptors (summary by Zangen et al., 2011).
By sequencing putative genes centromeric to the BRCA1 gene (113705) on chromosome 17, followed by screening a breast cancer cell line cDNA library, Rommens et al. (1995) cloned GT198. The deduced protein contains 203 amino acids. Northern blot analysis detected a 1.6-kb transcript in all adult and fetal tissues examined, with abundant expression in testis, colon, a breast cancer cell line, and a lymphoma.
Tanaka et al. (1997) cloned Gt198, which they called Tbpip, from a mouse testis cDNA library. The deduced 217-amino acid protein has several putative phosphorylation sites. RT-PCR detected Tbpip expression in CD4 (186940)-positive T cells and in macrophages. In situ hybridization found Tbpip mRNA colocalized with Tbp1 (186852) in seminiferous tubules of adult mouse testis. Western blot analysis detected Tbpip at an apparent molecular mass of 24 kD. Immunohistochemical analysis of mouse testis detected Tbpip in nuclei of primary and secondary spermatocytes.
By PCR using primers designed from mouse Tbpip, Ijichi et al. (2000) cloned full-length human TBPIP from breast cancer cell line mRNA and a testis cDNA library. The deduced 217-amino acid protein contains an acidic region near the C terminus and several putative phosphorylation sites. Mouse and human TBPIP share 88% amino acid homology.
By genomic sequence analysis, Rommens et al. (1995) mapped the TBPIP gene to chromosome 17q21. Using radiation hybrid analysis, Ijichi et al. (2000) mapped the TBPIP gene to chromosome 17q12-q21.
The human immunodeficiency virus-1 (HIV-1) regulatory protein Tat is essential for HIV-1 gene expression and replication in infected cells. TBP1 is a cellular protein that suppresses Tat-mediated transactivation of HIV replication. Tanaka et al. (1997) found that mouse Tbpip synergistically cooperated with Tbp1 to suppress Tat-mediated transactivation of the HIV-1 long terminal repeat promoter.
Ijichi et al. (2000) showed that human TBPIP interacted directly with TBP1 and enhanced TBP1-mediated inhibition of HIV Tat-mediated transactivation.
Enomoto et al. (2006) demonstrated that coexpression of human MND1 (611422) and HOP2 in E. coli resulted in the formation of stable heterodimers. The HOP2-MND1 complex stimulated DMC1 (602721)- and RAD51 (179617)-mediated DNA strand exchange, and preferentially bound to a 3-stranded DNA branch, which mimics the strand-exchange intermediate. Enomoto et al. (2006) concluded that the HOP2-MND1 complex may ensure proper pairing between homologous chromosomes by stimulating strand exchange during meiosis.
Chi et al. (2007) found that the Hop2 component of the mouse recombinant Hop2-Mnd1 complex was the major DNA-binding subunit, and that Mnd1 was the Rad51-interacting entity. Hop2-Mnd1 stabilized the Rad51-single-stranded DNA (ssDNA) nucleoprotein filament, and enhanced the ability of the Rad51-ssDNA nucleoprotein filament to capture duplex DNA, which is an obligatory step in the formation of the synaptic complex critical for DNA joint formation. Pezza et al. (2007) showed that the mouse Hop2-Mnd1 complex stimulated Dmc1 to promote synaptic complex formation on long duplex DNAs. Synaptic alignment was a consequence of the ability of Hop2-Mnd1 to stabilize the Dmc1-ssDNA nucleoprotein complex and facilitate the conjoining of DNA molecules through the capture of double-stranded DNA by the Dmc1-ssDNA nucleoprotein filament.
In a large consanguineous Arab Palestinian pedigree with hypergonadotropic ovarian dysgenesis mapping to chromosome 17 (ODG3; 614324), Zangen et al. (2011) analyzed candidate genes and identified homozygosity for a 3-bp deletion in the PSMC3IP gene (608665.0001) that segregated with disease in the family. In cell lines, the glu201del mutation abolished PSMC3IP activation of estrogen-driven transcription.
Petukhova et al. (2003) found that Hop2 knockout mice showed no gross anomalies in somatic tissues but developed a profound deficiency in gametogenesis. Hop2 -/- spermatocytes arrested at the stage of pachytene-like chromosome condensation. Axial elements were fully developed, but synapsis was limited. While meiotic double-stranded breaks were formed and processed in Hop2 -/- mice, they failed to be repaired.
In affected members of a large consanguineous Arab Palestinian pedigree with hypergonadotropic ovarian dysgenesis (ODG3; 614324), Zangen et al. (2011) identified homozygosity for an in-frame 3-bp deletion in the acceptor splice junction of exon 8 of the PSMC3IP gene, resulting in deletion of glu201. The unaffected parents were heterozygous for the deletion, which was not found in 254 ethnically matched chromosomes. RT-PCR analysis of leukocyte DNA from affected and unaffected family members showed no alternative splicing, suggesting that the mutation does not affect PSMC3IP splicing. Transfection studies in the IGROV1 ovarian carcinoma and MCF7 breast cancer cell lines demonstrated that the glu201del mutation abolished PSMC3IP activation of estrogen-driven transcription.
Chi, P., San Filippo, J., Sehorn, M. G., Petukhova, G. V., Sung, P. Bipartite stimulatory action of the Hop2-Mnd1 complex on the Rad51 recombinase. Genes Dev. 21: 1747-1757, 2007. [PubMed: 17639080] [Full Text: https://doi.org/10.1101/gad.1563007]
Enomoto, R., Kinebuchi, T., Sato, M., Yagi, H., Kurumizaka, H., Yokoyama, S. Stimulation of DNA strand exchange by the human TBPIP/Hop2-Mnd1 complex. J. Biol. Chem. 281: 5575-5581, 2006. [PubMed: 16407260] [Full Text: https://doi.org/10.1074/jbc.M506506200]
Ijichi, H., Tanaka, T., Nakamura, T., Yagi, H., Hakuba, A., Sato, M. Molecular cloning and characterization of a human homologue of TBPIP, a BRCA1 locus-related gene. Gene 248: 99-107, 2000. [PubMed: 10806355] [Full Text: https://doi.org/10.1016/s0378-1119(00)00141-4]
Petukhova, G. V., Romanienko, P. J., Camerini-Otero, R. D. The Hop2 protein has a direct role in promoting interhomolog interactions during mouse meiosis. Dev. Cell 5: 927-936, 2003. [PubMed: 14667414] [Full Text: https://doi.org/10.1016/s1534-5807(03)00369-1]
Pezza, R. J., Voloshin, O. N., Vanevski, F., Camerini-Otero, R. D. Hop2/Mnd1 acts on two critical steps in Dmc1-promoted homologous pairing. Genes Dev. 21: 1758-1766, 2007. [PubMed: 17639081] [Full Text: https://doi.org/10.1101/gad.1562907]
Rommens, J. M., Durocher, F., McArthur, J., Tonin, P., LeBlanc, J.-F., Allen, T., Samson, C., Ferri, L., Narod, S., Morgan, K., Simard, J. Generation of a transcription map at the HSD17B locus centromeric to BRCA1 at 17q21. Genomics 28: 530-542, 1995. [PubMed: 7490091] [Full Text: https://doi.org/10.1006/geno.1995.1185]
Tanaka, T., Nakamura, T., Takagi, H., Sato, M. Molecular cloning and characterization of a novel TBP-1 interacting protein (TBPIP): enhancement of TBP-1 action on Tat by TBPIP. Biochem. Biophys. Res. Commun. 239: 176-181, 1997. [PubMed: 9345291] [Full Text: https://doi.org/10.1006/bbrc.1997.7447]
Zangen, D., Kaufman, Y., Zeligson, S., Perlberg, S., Fridman, H., Kanaan, M., Abdulhadi-Atwan, M., Abu Libdeh, A., Gussow, A., Kisslov, I., Carmel, L., Renbaum, P., Levy-Lahad, E. XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription. Am. J. Hum. Genet. 89: 572-579, 2011. [PubMed: 21963259] [Full Text: https://doi.org/10.1016/j.ajhg.2011.09.006]