The MED12 gene, or mediator complex subunit 12, provides instructions for creating a protein. This protein is involved in numerous basic cellular processes, including cell growth, movement, and differentiation. It also contributes to early development, such as the formation of nerve cells in the brain.
The Core Function of MED12
The MED12 protein is an integral part of the “Mediator complex,” an assembly of approximately 25 proteins regulating gene activity. This complex acts as a physical link, connecting transcription factors—proteins that control whether genes are turned on or off—with RNA polymerase II, an enzyme that initiates gene transcription. Gene transcription uses DNA information to build proteins.
The Mediator complex ensures that genes are turned “on” or “off” at the appropriate times, which is necessary for proper cell function and development. MED12 is part of the kinase module within the Mediator complex, which also includes MED13, CyclinC (CycC), and CDK8. This module plays a role in activating and repressing transcription by regulating RNA polymerase II.
MED12’s Link to Human Conditions
Mutations in the MED12 gene have been associated with a range of human conditions and disorders, highlighting the broad impact of this gene on health. These conditions span from developmental disorders to the formation of tumors.
Two X-linked intellectual disabilities, FG Syndrome and Lujan-Fryns Syndrome, are linked to MED12 mutations. FG syndrome involves intellectual disability, behavioral problems, weak muscle tone, and physical abnormalities like obstruction of the anal opening. Lujan-Fryns syndrome also involves intellectual disability and behavioral issues, along with physical features such as tall stature and a long, narrow face.
MED12 mutations are frequently found in uterine fibroids, also known as leiomyomas, which are common benign tumors in women of reproductive age. These growths can cause pelvic pain, abnormal bleeding, and sometimes infertility. Somatic MED12 mutations are present in a significant percentage of uterine fibroids, with an average prevalence of about 55.8% globally, although this can vary between 31.1% and 80% in different studies.
MED12 mutations also play a role in certain cancers. These include breast cancer, specifically breast fibroadenomas and phyllodes tumors, and desmoid tumors. Somatic MED12 mutations have been identified in cancerous uterine tumors, such as leiomyosarcomas, and in some prostate and colorectal cancers. Additionally, MED12 mutations have been observed in other cancers like ovarian carcinoma, melanoma, pancreatic carcinoma, and non-small cell lung carcinoma.
How MED12 Changes Lead to Disease
Mutations in the MED12 gene lead to an altered MED12 protein, which can disrupt the normal function of the Mediator complex. These altered proteins can interfere with the complex’s ability to activate or repress genes, leading to misregulation of cellular processes.
In FG and Lujan syndromes, specific MED12 mutations, such as Arg961Trp (R961W) and Asn1007Ser (N1007S), disrupt the Mediator complex’s control over the Sonic Hedgehog (SHH) signaling pathway. This disruption can lead to an enhanced activation of this pathway, contributing to the craniofacial anomalies and multiple organ malformations. These mutations can also affect the Mediator complex’s ability to recruit G9a, a protein involved in epigenetic regulation, leading to abnormal neuronal gene expression.
In uterine fibroids, MED12 mutations, particularly a heterozygous missense mutation affecting codon 44 of exon 2 (nucleotide 131), are common. These mutations are reported to act by increasing levels of AKT and disrupting the activity of the cyclin C-CDK8/19 kinase. This altered kinase activity leads to dysregulated gene expression and tumor growth in uterine fibroids. Some mutations can lead to a “loss of function,” where the protein works less effectively, while others might cause a “gain of function” or “dominant-negative” effect, where the altered protein interferes with normal proteins or gains a new, harmful activity.