PSMC3IP – 46,XX Complete Gonadal Dysgenesis

Biallelic loss-of-function variants in PSMC3IP have been implicated in 46,XX complete gonadal dysgenesis (46,XX-CGD), a disorder characterized by primary amenorrhea and ovarian failure. In a Chinese whole-exome sequencing study of 20 unrelated patients, one proband harbored a homozygous stop-gain variant c.489C>G (p.Tyr163Ter) (PMID:39529088). Further evidence emerged from a consanguineous Yemeni family in which four sisters with primary ovarian insufficiency shared the homozygous c.489C>G (p.Tyr163Ter) variant, with three additional affected relatives segregating the allele under an autosomal recessive model (PMID:29240891). There are thus at least five probands with homozygous PSMC3IP loss-of-function variants and segregation in one family, supporting a limited level of clinical validity.

No functional studies have directly examined PSMC3IP’s role in ovarian development or gonadal differentiation; existing assays focus on its tumor suppressor activities in cancer. The absence of tissue-specific functional validation precludes mechanistic insights for 46,XX-CGD. Nevertheless, the recurrent homozygous stop-gain variant strongly implicates haploinsufficiency in ovarian failure. Further in vitro or in vivo models are required to define PSMC3IP’s function in folliculogenesis. Key Take-Home: Inclusion of PSMC3IP in diagnostic gene panels for primary ovarian insufficiency may facilitate the identification of autosomal recessive 46,XX complete gonadal dysgenesis.

References

• N/A • N/A • Title not provided PMID:39529088
• The Journal of clinical endocrinology and metabolism • 2018 • Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation. PMID:29240891

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