MED13L, a subunit of the CDK8-associated mediator complex, is crucial for transcriptional regulation, functioning as a molecular interface between RNA polymerase II and gene-specific transcription factors [6,7]. As part of the Mediator complex, it has an essential role in controlling gene expression, which is vital for normal biological processes [2].

Genetic variants in MED13L can lead to an autosomal-dominant syndrome characterized by intellectual disability/developmental delay, facial dysmorphism, and often accompanied by speech delay [1]. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported, and paternal germinal mosaicism for a missense MED13L variant can cause the related intellectual disability syndrome [2]. In individuals with MED13L-related disorder, severe motor speech impairment is common, along with language, motor, and cognitive deficits, as well as medical features like hypotonia, vision problems, and recurrent otitis media [3]. In lung cancer, radiation can trigger the disassembly of the Mediator complex via the silencing of MED13L by miR-4497, which affects epigenetic control and radiosensitivity [4]. Also, levels of Enterococcus faecalis in the gut are associated with variants in the MED13L locus, which has been linked to colorectal cancer [5]. Disease-associated MED13L variants can influence the dendritic development of cerebral cortical neurons, with some variants affecting dendritic growth and spine formation [6].

In summary, MED13L is essential for transcriptional regulation and normal biological function. Its variants are significantly associated with intellectual disability-related syndromes, speech and motor deficits, and potentially with cancer-related processes such as lung cancer radiosensitivity and colorectal cancer. Studies on MED13L-related phenotypes in humans help to understand its role in disease-associated biological processes.

References:

1. Carvalho, L M L, da Costa, S S, Campagnari, F, Koiffmann, C P, Rosenberg, C. 2021. Two novel pathogenic variants in MED13L: one familial and one isolated case. In Journal of intellectual disability research : JIDR, 65, 1049-1057. doi:10.1111/jir.12891. https://pubmed.ncbi.nlm.nih.gov/34713510/

2. Bessenyei, Beáta, Balogh, István, Mokánszki, Attila, Pfundt, Rolph, Szakszon, Katalin. 2022. MED13L-related intellectual disability due to paternal germinal mosaicism. In Cold Spring Harbor molecular case studies, 8, . doi:10.1101/mcs.a006124. https://pubmed.ncbi.nlm.nih.gov/34654706/

3. Mitchel, Marissa Weyer, Turner, Stefanie, Walsh, Lauren K, Myers, Scott M, Taylor, Cora M. 2024. MED13L-related disorder characterized by severe motor speech impairment. In Research square, , . doi:10.21203/rs.3.rs-4790993/v1. https://pubmed.ncbi.nlm.nih.gov/39257968/

4. Zhang, Nasha, Song, Yemei, Xu, Yeyang, Yu, Jinming, Yang, Ming. 2020. MED13L integrates Mediator-regulated epigenetic control into lung cancer radiosensitivity. In Theranostics, 10, 9378-9394. doi:10.7150/thno.48247. https://pubmed.ncbi.nlm.nih.gov/32802198/

5. Qin, Youwen, Havulinna, Aki S, Liu, Yang, Inouye, Michael, Méric, Guillaume. 2022. Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort. In Nature genetics, 54, 134-142. doi:10.1038/s41588-021-00991-z. https://pubmed.ncbi.nlm.nih.gov/35115689/

6. Hamada, Nanako, Iwamoto, Ikuko, Nagata, Koh-Ichi. 2023. MED13L and its disease-associated variants influence the dendritic development of cerebral cortical neurons in the mammalian brain. In Journal of neurochemistry, 165, 334-347. doi:10.1111/jnc.15783. https://pubmed.ncbi.nlm.nih.gov/36798993/

7. Adegbola, Abidemi, Musante, Luciana, Callewaert, Bert, Kaindl, Angela M, Kalscheuer, Vera M. 2015. Redefining the MED13L syndrome. In European journal of human genetics : EJHG, 23, 1308-17. doi:10.1038/ejhg.2015.26. https://pubmed.ncbi.nlm.nih.gov/25758992/