title: Med12 gain-of-function mutation causes leiomyomas and genomic instability.
abstract: Uterine leiomyomas are benign tumors that can cause pain, bleeding, and infertility in some women. Mediator complex subunit 12 (MED12) exon 2 variants are associated with uterine leiomyomas; however, the causality of MED12 variants, their genetic mode of action, and their role in genomic instability have not been established. Here, we generated a mouse model that conditionally expresses a Med12 missense variant (c.131G>A) in the uterus and demonstrated that this alteration alone promotes uterine leiomyoma formation and hyperplasia in both WT mice and animals harboring a uterine mesenchymal cell-specific Med12 deletion. Compared with WT animals, expression of Med12 c.131G>A in conditional Med12-KO mice resulted in earlier onset of leiomyoma lesions that were also greater in size. Moreover, leiomyomatous, Med12 c.131G>A variant-expressing uteri developed chromosomal rearrangements. Together, our results show that the common human leiomyoma-associated MED12 variant can cause leiomyomas in mice via a gain of function that drives genomic instability, which is frequently observed in human leiomyomas.
authors.forename: Priya
authors.initials: P
authors.lastname: Mittal
authors.forename: Yong-Hyun
authors.initials: YH
authors.lastname: Shin
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Yatsenko
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Castro
authors.forename: Urvashi
authors.initials: U
authors.lastname: Surti
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rajkovic
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002869:Chromosome Aberrations; D005260:Female; D042822:Genomic Instability; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C460107:MED12 protein, human; C539582:Med12 protein, mouse; D056892:Mediator Complex; D009363:Neoplasm Proteins