title: 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.
authors.affiliation: Division of Pediatric Endocrinology, Hadassah Hebrew University Medical School, Jerusalem, Israel. zangend@hadassah.org.il
authors.forename: David
authors.initials: D
authors.lastname: Zangen
authors.forename: Yotam
authors.initials: Y
authors.lastname: Kaufman
authors.forename: Sharon
authors.initials: S
authors.lastname: Zeligson
authors.forename: Shira
authors.initials: S
authors.lastname: Perlberg
authors.forename: Hila
authors.initials: H
authors.lastname: Fridman
authors.forename: Moein
authors.initials: M
authors.lastname: Kanaan
authors.forename: Maha
authors.initials: M
authors.lastname: Abdulhadi-Atwan
authors.forename: Abdulsalam
authors.initials: A
authors.lastname: Abu Libdeh
authors.forename: Ayal
authors.initials: A
authors.lastname: Gussow
authors.forename: Irit
authors.initials: I
authors.lastname: Kisslov
authors.forename: Liran
authors.initials: L
authors.lastname: Carmel
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
mesh_terms: D041321:Chromosomes, Human, X; D003241:Consanguinity; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005819:Genetic Markers; D005838:Genotype; D006059:Gonadal Dysgenesis / Q000235:genetics*; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics; D006239:Haplotypes; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004967:Estrogens; D005819:Genetic Markers; D009687:Nuclear Proteins; C443678:PSMC3IP protein, human; D015534:Trans-Activators; D046988:Proteasome Endopeptidase Complex