Alternative titles; symbols
HGNC Approved Gene Symbol: MED17
Cytogenetic location: 11q21 Genomic coordinates (GRCh38) : 11:93,784,282-93,814,963 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q21 | Microcephaly, postnatal progressive, with seizures and brain atrophy | 613668 | Autosomal recessive | 3 |
The Mediator is a multiprotein coactivator that is required by DNA-binding transcription factors for activation of polymerase II (see 180660)-transcribed genes. MED17 appears to be a core Mediator subunit and is found in nearly all Mediator preparations (summary by Sato et al., 2004).
Using a HeLa cell line, Ito et al. (1999) cloned TRAP80, the gene encoding the 80-kD subunit of the TRAP complex. (For background information on thyroid hormone receptor-associated proteins (TRAPs), see 300182). The TRAP80 cDNA encodes a 717-amino acid protein that has no obvious motifs other than a short leucine zipper in the middle of the sequence. The TRAP80 cDNA appears to be equivalent to the p78 component of the mouse Mediator (Jiang et al., 1998). Northern blot analysis of multiple human tissues showed that the TRAP80 gene is ubiquitously expressed as an approximately 3.0-kb transcript.
Gene transcription requires factors that recognize transcriptional enhancer sites in DNA. These factors work with coactivators to direct transcriptional initiation by the RNA polymerase II apparatus (see POLR2A, 180660). Transcriptional activation by enhancer-binding factors such as SP1 (189906) requires interaction with the TFIID complex (see TAF2A, 313650). To identify other potential SP1 cofactors, Ryu et al. (1999) developed an in vitro transcription assay consisting of TFIIA (GTF2A1; 600520), RNA polII, and the basal transcription factors GTF2B (189963), GTF2E (189962), GTF2F (189968), and GTF2H (189972), supplemented with TFIID or TBP (600075). By sequential chromatography, they excluded PC4 (600503) as an SP1 cofactor and identified a multisubunit cofactor, CRSP (cofactor required for SP1 activation), which, along with TFIID, is required for efficient activation by SP1. CRSP behaves as a single complex of approximately 700 kD. Ryu et al. (1999) tentatively identified 9 polypeptides as CRSP subunits (see also PPARBP, 604311). Using microsequence peptide analysis, they cloned a CRSP cDNA encoding a 77-kD protein, CRSP6, which they termed CRSP77.
p21 (CDKN1A; 116899) is a key mediator of p53 (TP53; 191170)-dependent cell cycle arrest. Donner et al. (2007) found that transcriptional activity of the p21 promoter in human cell lines varied in response to distinct p53-activating stimuli. Core Mediator subunits MED1 (PPARBP; 604311) and MED17 were recruited to the p21 gene regardless of the p53-activating stimuli used. In contrast, 3 subunits of the CDK module of Mediator, CDK8 (603184), MED12 (300188), and cyclin C (CCNC; 123838), were recruited following treatment with nutlin-3, a nongenotoxic drug that activates p53, but not in response to DNA damage induced by ultraviolet light C.
Soutourina et al. (2011) identified a direct physical interaction between the Rpb3 Pol II subunit of S. cerevisiae (see 180663) and the essential Mediator subunit Med17. They also demonstrated a functional element in the Mediator-Pol II interface that is important for genomewide Pol II recruitment in vivo. Soutourina et al. (2011) concluded that a direct interaction between Mediator and Pol II is generally required for transcription of class II genes in eukaryotes.
The International Radiation Hybrid Mapping Consortium mapped the MED17 gene to chromosome 11 (WI-15663).
By candidate gene sequencing of 5 patients from 4 families with postnatal progressive microcephaly, seizures, and brain atrophy (613668), Kaufmann et al. (2010) identified a homozygous mutation in the MED17 gene (L371P; 603810.0001). Screening of additional patients with a similar disorder identified the same homozygous mutation in 4 more patients. All affected individuals were of Caucasus Jewish origin, indicating a founder effect. The L371P mutation was found in the heterozygous state in 4 of 76 unaffected individuals in this population. The mutation was not found in 110 individuals of Ashkenazi Jewish origin or in 113 individuals of Arab Moslem origin. In vitro functional expression assays in yeast, using the corresponding yeast mutation M504P, showed that the mutant MED17 protein was functionally inactive.
By candidate gene sequencing of 5 patients from 4 families with postnatal progressive microcephaly, seizures, and brain atrophy (613668), Kaufmann et al. (2010) identified a homozygous 1112T-C transition in exon 7 of the MED17 gene, resulting in a leu371-to-pro (L371P) substitution. The disorder was characterized by normal head circumference at birth, but onset of postnatal microcephaly and severe developmental retardation beginning between 4 and 9 weeks of life. Patients showed spasticity and seizures, and brain imaging showed severe brain atrophy and myelination defects. Screening of additional patients with a similar disorder identified the same homozygous mutation in 4 more patients. All affected individuals were of Caucasus Jewish origin, indicating a founder effect. In vitro functional expression assays in yeast, using the corresponding yeast mutation M504P, showed that the mutant MED17 protein was functionally inactive. The L371P mutation was found in the heterozygous state in 4 of 76 unaffected individuals in the Caucasus Jewish population. The mutation was not found in 110 individuals of Ashkenazi Jewish origin or in 113 individuals of Arab Moslem origin.
Donner, A. J., Szostek, S., Hoover, J. M., Espinosa, J. M. CDK8 is a stimulus-specific positive coregulator of p53 target genes. Molec. Cell 27: 121-133, 2007. [PubMed: 17612495] [Full Text: https://doi.org/10.1016/j.molcel.2007.05.026]
Ito, M., Yuan, C.-X., Malik, S., Gu, W., Fondell, J. D., Yamamura, S., Fu, Z.-Y., Zhang, X., Qin, J., Roeder, R. G. Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators. Molec. Cell 3: 361-370, 1999. [PubMed: 10198638] [Full Text: https://doi.org/10.1016/s1097-2765(00)80463-3]
Jiang, Y.-W., Veschambre, P., Erdjument-Bromage, H., Tempst, P., Conaway, J. W., Conaway, R. C., Kornberg, R. D. Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc. Nat. Acad. Sci. 95: 8538-8543, 1998. [PubMed: 9671713] [Full Text: https://doi.org/10.1073/pnas.95.15.8538]
Kaufmann, R., Straussberg, R., Mandel, H., Fattal-Valevski, A., Ben-Zeev, B., Naamati, A., Shaag, A., Zenvirt, S., Konen, O., Mimouni-Bloch, A., Dobyns, W. B., Edvardson, S., Pines, O., Elpeleg, O. Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex. Am. J. Hum. Genet. 87: 667-670, 2010. [PubMed: 20950787] [Full Text: https://doi.org/10.1016/j.ajhg.2010.09.016]
Ryu, S., Zhou, S., Ladurner, A. G., Tjian, R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397: 446-450, 1999. [PubMed: 9989412] [Full Text: https://doi.org/10.1038/17141]
Sato, S., Tomomori-Sato, C., Parmely, T. J., Florens, L., Zybailov, B., Swanson, S. K., Banks, C. A. S., Jin, J., Cai, Y., Washburn, M. P., Conaway, J. W., Conaway, R. C. A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology. Molec. Cell 14: 685-691, 2004. [PubMed: 15175163] [Full Text: https://doi.org/10.1016/j.molcel.2004.05.006]
Soutourina, J., Wydau, S., Ambroise, Y., Boschiero, C., Werner, M. Direct interaction of RNA polymerase II and Mediator required for transcription in vivo. Science 331: 1451-1454, 2011. [PubMed: 21415355] [Full Text: https://doi.org/10.1126/science.1200188]