MED12L is a gene that plays a crucial role in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. It is highly conserved across eukaryotes and contains 43 exons. The protein encoded by MED12L is a component of the Mediator complex, which is involved in linking gene-specific transcription activators with the basal transcription machinery. The Mediator complex is composed of 30 subunits organized into four modules: Kinase, Head, Middle, and Tail. MED12L is predicted to be a subunit of the kinase module, along with MED12, MED13, MED13L, CDK8, CDK19, and Cyclin C.

Mediator Complex and Its Components

The Mediator complex is essential for the regulation of gene expression. It serves as a bridge, conveying information from gene-specific regulatory proteins to the RNA polymerase II machinery, thereby facilitating the transcription of nearly all protein-coding genes. The complex is divided into four main modules:

1. Head Module: This module interacts directly with RNA polymerase II, playing a critical role in the formation and stability of the preinitiation complex. Key subunits in this module include MED6, MED8, MED11, MED17, MED18, MED20, and MED22.

2. Middle Module: The middle module serves as a structural scaffold, supporting interactions between other modules and the RNA polymerase II complex. Important subunits in this module are MED1, MED4, MED7, MED9, MED10, MED19, MED21, and MED31.

3. Tail Module: This module primarily interacts with gene-specific transcription factors, facilitating the recruitment of the Mediator complex to specific promoters. Key subunits include MED2, MED3, MED14, MED15, MED16, MED23, MED24, and MED25.

4. Kinase Module: The kinase module, which includes MED12, MED13, MED12L, MED13L, CDK8, CDK19, and Cyclin C, is reversibly associated with the core Mediator complex. It is involved in both transcriptional repression and activation. By phosphorylating different target proteins, the kinase module can change how the Mediator complex and RNA polymerase II work.

Genetic Variants and Disease

Variants in the subunits of the Mediator kinase module have been linked to several human diseases, particularly those affecting neurological development. The following sections describe the role of these variants in different conditions.

MED12

MED12 variants are associated with several X-linked intellectual disability syndromes, including Opitz–Kaveggia (FG) syndrome, Lujan–Fryns syndrome, and Ohdo syndrome, Maat–Kievit–Brunner type. Missense variants in MED12 that disrupt gene expression are the root cause of these conditions. Common features include:

• Intellectual disability
• Behavior abnormalities
• Autism spectrum disorders
• Corpus callosum anomalies
• Macrocephaly
• Tall forehead
• Hypotonia

MED13

Variants in MED13 have been reported in individuals with mild to moderate intellectual disabilities and speech disorders. Other features include autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart defects, and distinctive facial features.

MED13L

MED13L variants cause moderate to severe intellectual disability and severe speech disorders. Over 60 individuals with these variants have been reported. Common features include:

• Intellectual disability
• Speech disorders
• Hypotonia
• Autism and behavioral disorders
• Corpus callosum hypoplasia or agenesis
• Various malformations

CDK19

Disruption of CDK19 has been reported in an individual with intellectual disability, microcephaly, and bilateral congenital retinal folds. This indicates a distinct neurological phenotype associated with CDK19 variants.

Clinical Features of MED12L Variants

Mathilde Nizon et al. (2019) studied seven individuals with genetic changes in the MED12L gene, including copy-number variants (CNVs) and single-nucleotide variants (SNVs). These changes included duplications, deletions, and single-nucleotide variants, most of which were de novo (not inherited from parents). All individuals had neurological problems, primarily intellectual disability or developmental delay and speech impairment. Some also showed abnormal behavior, corpus callosum agenesis, and mild facial features. No clear link between the specific genetic changes and the symptoms could be identified.

Functional Studies

Studies on the fibroblasts of two French patients showed transcriptional errors, which suggests that these MED12L changes cause a loss of function (haploinsufficiency) that affects gene transcription.

RNA Synthesis Recovery

Researchers looked at how quickly RNA can be made again after being exposed to UV light and found that fibroblasts from people with MED12L variants recovered from UV light less quickly than normal cells. Individuals with MED12 mutations had moderately decreased recovery levels, similar to individuals with MED12 mutations, while those with MED13L mutations had more severely decreased levels, similar to cells with CSA defects. This indicates that mutations in these genes affect the cells' ability to repair and synthesize RNA after UV damage.

Conclusion

Like other parts of the kinase module, MED12L can cause disease in humans by messing up transcription. It can be hard to tell the difference between intellectual disability syndromes based on clinical phenotype alone, but there is a pattern that shows up for disorders that are caused by transcriptional problems connected to the mediator complex. Harmful variations in Mediator kinase module subunits make transcriptional coactivation less effective, which causes the observed phenotypes in certain situations during development and after birth. 

Reference

Nizon M, Laugel V, Flanigan KM, Pastore M, Waldrop MA, Rosenfeld JA (2019) Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect. Genet Med 21 (12):2713-2722. DOI: 10.1038/s41436-019-0557-3 PMID: 31155615.