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XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven

David Zangen1, Yotam Kaufman, Sharon Zeligson

  • 1Division of Pediatric Endocrinology, Hadassah Hebrew University Medical School, Jerusalem, Israel. zangend@hadassah.org.il

American Journal of Human Genetics
|October 4, 2011
PubMed

Insights

Genetic mutations in the PSMC3IP gene cause female gonadal dysgenesis (XX-GD), a disorder affecting puberty and ovarian development. This finding highlights PSMC3IP

Area of Science:

  • Genetics and Molecular Biology
  • Reproductive Endocrinology
  • Developmental Biology

Background:

  • Female gonadal dysgenesis (XX-GD) is a rare disorder characterized by primary amenorrhea and hypergonadotropic hypogonadism due to streak gonads.
  • The genetic underpinnings of most XX-GD cases remain unexplained, though autosomal recessive inheritance is suspected.
  • Previous research identified mutations in FSH receptor and BMP15 as causes of XX-GD, implicating hormonal signaling pathways.

Observation:

  • A consanguineous Palestinian family with multiple affected females exhibiting XX-GD was studied.
  • Homozygosity mapping and whole-exome sequencing identified a homozygous 3 bp deletion (c.600_602del) in the PSMC3IP gene in affected individuals.
  • This mutation results in the deletion of a glutamic acid residue (p.Glu201del) in a critical C-terminal domain of the PSMC3IP protein.

Findings:

  • The PSMC3IP protein (Proteasome 26S subunit, ATPase, 3-Interacting Protein) is crucial for meiotic recombination and coactivates nuclear receptor-mediated transcription.
  • The identified p.Glu201del mutation in PSMC3IP impaired its ability to activate estrogen-driven transcription in cellular assays.
  • Mutations in PSMC3IP disrupt estrogenic signaling, impacting follicular pool development and counteracting follicular atresia, leading to ovarian dysgenesis.

Implications:

  • PSMC3IP is identified as a novel gene implicated in XX-GD, underscoring the critical role of hormonal signaling in ovarian development.
  • The findings suggest a common pathway involving PSMC3IP, FSH receptor, and BMP15 that, when perturbed, leads to isolated XX-GD.
  • PSMC3IP is proposed as a candidate gene for premature ovarian failure, warranting further investigation into its role in folliculogenesis.

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