Med12 gain-of-function mutation causes leiomyomas and genomic instability

Area of Science:

• Reproductive biology
• Genetics
• Oncology

Background:

• Uterine leiomyomas, common benign tumors, cause significant morbidity.
• Mediator complex subunit 12 (MED12) exon 2 variants are linked to leiomyomas, but their causal role and mechanism remain unclear.
• The role of MED12 variants in uterine leiomyoma pathogenesis and genomic instability requires elucidation.

Purpose of the Study:

• To investigate the causality of MED12 variants in uterine leiomyoma formation.
• To determine the genetic mode of action and role in genomic instability of MED12 variants.
• To establish a preclinical mouse model for studying MED12-driven uterine leiomyomas.

Main Methods:

• Generation of a mouse model with conditional uterine expression of a Med12 missense variant (c.131G>A).
• Assessment of uterine leiomyoma formation and hyperplasia in wild-type (WT) and Med12-deficient mice.
• Analysis of chromosomal rearrangements in leiomyomatous uteri expressing the Med12 variant.

Main Results:

• The Med12 c.131G>A variant alone induced uterine leiomyoma formation and hyperplasia in mice.
• Conditional Med12-knockout (KO) mice expressing the variant showed earlier onset and larger leiomyoma lesions compared to WT.
• Leiomyomas with the Med12 c.131G>A variant exhibited chromosomal rearrangements, indicating genomic instability.

Conclusions:

• The common human MED12 leiomyoma-associated variant acts via a gain-of-function mechanism.
• This gain-of-function promotes uterine leiomyoma development and drives genomic instability.
• The mouse model validates MED12 as a key driver of uterine leiomyomas and associated genomic instability.