Alternative titles; symbols
HGNC Approved Gene Symbol: MED23
Cytogenetic location: 6q23.2 Genomic coordinates (GRCh38) : 6:131,573,966-131,628,313 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q23.2 | Intellectual developmental disorder, autosomal recessive 18, with or without epilepsy | 614249 | Autosomal recessive | 3 |
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 130-kD protein, CRSP3, which they termed CRSP130.
Sur2 is a metazoan Mediator (see 602984) subunit that interacts with the adenovirus E1A protein and functions in a mitogen-activated protein kinase pathway required for vulva development in C. elegans. Stevens et al. (2002) generated Sur2 -/- embryonic stem cells to analyze its function as a mammalian Mediator component. Their results demonstrated that Sur2 forms a subcomplex of the Mediator with 2 other subunits, TRAP/Med100 and Med95 (604062). Knockout of Sur2 prevented activation by E1A-CR3 and the mitogen-activated protein kinase-regulated ETS transcription factor Elk1 (311040), but not by multiple other transcription factors. Stevens et al. (2002) concluded that specific activation domains stimulate transcription by binding to distinct Mediator subunits. Activation by E1A and Elk1 requires recruitment of Mediator to a promoter by binding to its Sur2 subunit.
In a family with 5 of 8 children segregating autosomal recessive intellectual developmental disorder-18 without epilepsy (MRT18; 614249), Hashimoto et al. (2011) identified a homozygous missense mutation in the MED23 gene (R617Q; 605042.0001). Arg617 is absolutely conserved across all MED23 orthologs from Xenopus to Drosophila and human. The R617Q mutation specifically impaired the response of JUN (165160) and FOS (164810) immediate-early genes to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4, 602272 and ELK1, 311040, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurologic disorders linked to mutations in other Mediator subunits or proteins interacting with the Mediator complex. Hashimoto et al. (2011) concluded that their findings highlighted the crucial role of Mediator in brain development and functioning and suggested that altered immediate-early gene expression might be a common molecular hallmark of cognitive deficit.
In 2 brothers, born of nonconsanguineous parents, with MRT18 with epilepsy, Trehan et al. (2015) identified compound heterozygous mutations in the MED23 gene (H1219R, 605042.0002; R1336X, 605042.0003). Both brothers showed epileptiform abnormalities but did not have clinical seizures. MED23 expression was normal in patient fibroblasts, but expression of JUN and FOS in response to serum mitogen stimulation was reduced and increased, respectively, compared to controls.
In a 7-year-old boy, born of consanguineous parents, with MRT18 with epilepsy, Lionel et al. (2016) identified a homozygous mutation in the MED23 gene (Q646R; 605042.0004). The mutation was identified by whole-exome sequencing.
In a 25-year-old man, born to consanguineous Iranian parents, with MRT18 without epilepsy, Hashemi-Gorji et al. (2019) identified a homozygous missense mutation in the MED23 gene (R224G; 605042.0006). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In 3 Pakistani sibs with MRT18 without epilepsy, Riazuddin et al. (2017) identified a homozygous missense mutation in the MED23 gene (Y169C; 605042.0005). The mutation, which was found by whole-exome sequencing, was present in heterozygous state in the parents. The sibs were identified from a cohort of 121 consanguineous Pakistani families segregating impaired intellectual development.
In a 5-year-old boy with MRT18 with epilepsy, Demos et al. (2019) identified compound heterozygous mutations in the MED23 gene (G128R, 605042.0007; A180D, 605042.0008). The mutations were found by whole-exome sequencing, and the parents were shown to be carriers. The patient was identified from a cohort of 180 patients with early-onset epilepsy.
In a large Algerian consanguineous family in which 5 affected individuals presented with autosomal recessive intellectual developmental disorder-18 without epilepsy (MRT18; 614249), Hashimoto et al. (2011) identified homozygosity for a G-to-A transition at nucleotide 1850 of the MED23 gene, resulting in an arg-to-gln substitution at codon 617 (R617Q). This mutation cosegregated with the disease and was not present in 608 control chromosomes including 242 chromosomes from individuals of Algerian origin.
In 2 sibs with autosomal recessive intellectual developmental disorder-18 with epilepsy (MRT18; 614249), Trehan et al. (2015) identified compound heterozygous mutations in the MED23 gene: a c.3656A-G transition (c.3656A-G, NM_015979.3), resulting in a his1219-to-arg (H1219R) substitution, and a c.4006C-T transition, resulting in an arg1336-to-ter (R1336X; 605042.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were present in heterozygous state in the parents. Both brothers had epileptiform abnormalities but did not have clinical seizures.
For discussion of the c.4006C-T transition (c.4006C-T, NM_015979.3) in the MED23 gene, resulting in an arg1336-to-ter (R1336X) substitution, that was found in compound heterozygous state in 2 sibs with autosomal recessive intellectual developmental disorder-18 with epilepsy (MRT18; 614249) by Trehan et al. (2015), see 605042.0002.
In a 7-year-old boy, born to consanguineous parents, with autosomal recessive intellectual developmental disorder-18 with epilepsy (MRT18; 614249), Lionel et al. (2016) identified a homozygous c.1937A-G transition (c.1937A-G, NM_015979) in the MED23 gene, resulting in a gln646-to-arg (Q646R) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was present in the ExAC database at a frequency of 8.23e-06. Functional studies were not performed.
In 3 sibs, born to consanguineous Pakistani parents (family PKMR85), with autosomal recessive intellectual developmental disorder-18 without epilepsy (MRT18; 614249), Riazuddin et al. (2017) identified homozygosity for a c.506A-G transition (c.506A-G, NM_004830.3) in the MED23 gene, resulting in a tyr169-to-cys (Y169C) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the ExAC database or in a database of 213 unrelated, ethnically matched controls. Functional studies were not performed.
In a 25-year-old Iranian man, born to consanguineous parents, with autosomal recessive intellectual developmental disorder-18 without epilepsy (MRT18; 614249), Hashemi-Gorji et al. (2019) identified homozygosity for a c.670C-G transversion (c.670C-G, NM_015979.3) in the MED23 gene, resulting in an arg224-to-gly (R224G) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the 1000 Genomes Project, ESP6500, EVS, ExAC, and Iranome databases or in an in-house Iranian exome database. Functional studies were not performed.
In a 5-year-old boy (patient 069) with autosomal recessive intellectual developmental disorder-18 with epilepsy (MRT18; 614249), Demos et al. (2019) identified compound heterozygous mutations in the MED23 gene: a c.382G-A transition (c.382G-A, NM_015979), resulting in a gly128-to-arg (G128R) substitution, and a c.539C-A transversion, resulting in an ala180-to-asp (A180D; 605042.0008) substitution. The mutations were identified by whole-exome sequencing, and the parents were shown to be mutation carriers. Functional studies were not performed. The patient had a similarly affected brother. The patient was identified from a cohort of 180 patients with early-onset epilepsy.
For discussion of the c.539C-A transversion (c.539C-A, NM_015979) in the MED23 gene, resulting in an ala180-to-asp (A180D) substitution, that was found in compound heterozygous state in a patient with autosomal recessive intellectual developmental disorder-18 with epilepsy by Demos et al. (2019), see 605042.0007.
Demos, M., Guella, I., DeGuzman, C., McKenzie, M. B., Buerki, S. E., Evans, D. M., Toyota, E. B., Boelman, C., Huh, L. L., Datta, A., Michoulas, A., Selby, K., and 13 others. Diagnostic yield and treatment impact of targeted exome sequencing in early-onset epilepsy. Front. Neurol. 10: 434, 2019. [PubMed: 31164858] [Full Text: https://doi.org/10.3389/fneur.2019.00434]
Hashemi-Gorji, F., Fardaei, M., Tabei, S. M. B., Miryounesi, M. Novel mutation in the MED23 gene for intellectual disability: a case report and literature review. Clin. Case Rep. 7: 331-335, 2019. [PubMed: 30847200] [Full Text: https://doi.org/10.1002/ccr3.1942]
Hashimoto, S., Boissel, S., Zarhrate, M., Rio, M., Munnich, A., Egly, J.-M., Colleaux, L. MED23 mutation links intellectual disability to dysregulation of immediate early gene expression. Science 333: 1161-1163, 2011. [PubMed: 21868677] [Full Text: https://doi.org/10.1126/science.1206638]
Lionel, A. C., Monfared, N., Scherer, S. W., Marshall, C. R., Mercimek-Mahmutoglu, S. MED23-associated refractory epilepsy successfully treated with the ketogenic diet. Am. J. Med. Genet. 170A: 2421-2425, 2016. [PubMed: 27311965] [Full Text: https://doi.org/10.1002/ajmg.a.37802]
Riazuddin, S., Hussain, M., Razzaq, A., Iqbal, Z., Shahzad, M., Polla, D. L., Song, Y., van Beusekom, E., Khan, A. A., Tomas-Roca, L., Rashid, M., Zahoor, M. Y., and 23 others. Exome sequencing of Pakistani consanguineous families identified 30 novel candidate genes for recessive intellectual disability. Molec. Psychiat. 22: 1604-1614, 2017. Note: Erratum: Molec. Psychiat. 25: 3101-3102, 2020. [PubMed: 27457812] [Full Text: https://doi.org/10.1038/mp.2016.109]
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]
Stevens, J. L., Cantin, G. T., Wang, G., Shevchenko, A., Shevchenko, A., Berk, A. J. Transcription control by E1A and MAP kinase pathway via Sur2 Mediator subunit. Science 296: 755-758, 2002. [PubMed: 11934987] [Full Text: https://doi.org/10.1126/science.1068943]
Trehan, A., Brady, J. M., Maduro, V., Bone, W. P., Huang, Y., Golas, G. A., Kane, M. S., Lee, P. R., Thurm, A., Gropman, A. L., Paul, S. M., Vezina, G., Markello, T. C., Gahl, W. A., Boerkoel, C. F., Tifft, C. J. MED23-associated intellectual disability in a non-consanguineous family. Am. J. Med. Genet. 167A: 1374-1380, 2015. [PubMed: 25845469] [Full Text: https://doi.org/10.1002/ajmg.a.37047]