A rare germline TXNIP missense mutation may contribute to the genesis of Familial ovarian mature teratoma in human.

Ovarian mature teratoma (OT) is a common ovarian germ cell tumor, and its early onset, multifocality, recurrence and familial aggregation suggest that genetic susceptibility contributes to a subset of cases. Whole-exome sequencing was used to identify candidate susceptibility variants in a family with recurrent and multifocal OT. A rare heterozygous germline TXNIP variant, NM_006472.6:c.1049C>T (p.Pro350Leu), was identified and confirmed by Sanger sequencing. p.Pro350Leu TXNIP showed lower steady-state abundance, faster cycloheximide-chase decay, and greater K48-linked polyubiquitination than wild-type TXNIP. Familial OT specimens also showed weaker TXNIP staining and stronger GLUT1 staining than sporadic OT specimens. TXNIP depletion increased plasma-membrane GLUT1, glucose uptake, lactate production and hyperactivated the PI3K/mTOR pathway, and familial tissues reproduced this PI3K/mTOR-dominant state. To our knowledge, this is the first genomic and functional investigation of a germline susceptibility mechanism for human familial ovarian mature teratoma. These findings establish TXNIP as the first functional candidate susceptibility gene for this phenotype and connect inherited susceptibility to ubiquitin-dependent protein turnover, GLUT1-driven metabolic reprogramming, and PI3K/mTOR-dominant follicular signaling.