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
Priya Mittal, Yong-hyun Shin, Svetlana A. Yatsenko, Carlos A. Castro, Urvashi Surti, Aleksandar Rajkovic
(A) Mouse model 2 (Med12Rmt/+Amhr2-Cre). A subset of cells that express Amhr2-Cre will express the Med12 c.131G>A variant from the autosomal ROSA locus in the presence of X chromosome WT Med12. Transcription from a mutant autosome (Amt/+) is shown with an arrow, and the promoter region is depicted in green. The Med12 c.131G>A variant is depicted with a blue star. The red chromosome indicates the inactivated X chromosome. (B and D) Uteri from Med12Rmt/+ control mice that, in the absence of Amhr2-Cre, did not express the Med12 c.131G>A variant and showed normal cross-sectional histology. (C and E) Uteri from Med12Rmt/+Amhr2-Cre mice that expressed the Med12 c.131G>A variant and revealed leiomyoma-like lesions in approximately 47% (8 of 17) of the females, with a typically sparse nuclear arrangement, a nodular pattern of cellular growth, and ECM deposition (black dotted lines). EM, endometrium. Scale bars: 500 μm (B and C), 100 μm (D and E).