Alternative titles; symbols
HGNC Approved Gene Symbol: MED13
Cytogenetic location: 17q23.2 Genomic coordinates (GRCh38) : 17:61,942,605-62,065,278 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.2 | Intellectual developmental disorder, autosomal dominant 61 | 618009 | Autosomal dominant | 3 |
MED13 is a subunit of the large Mediator complex that functions with DNA-binding transcription factors and RNA polymerase II (see 180660) for gene activation (summary by Sato et al., 2004).
Using a HeLa cell line, Ito et al. (1999) cloned TRAP240, the gene encoding the 240-kD subunit of the TRAP complex. The TRAP240 cDNA encodes a 2,174-amino acid protein that shows a regional identity of 29% and a similarity of 46% with a hypothetical C. elegans protein (CEK08F8 and CEF07H5). It shows no obvious relationship with known consensus sequences, other than 2 ligand-dependent nuclear hormone receptor signature recognition motifs (LXXLL sequences) at positions 1188-1192 and 1279-1283, and a short leucine zipper at position 1331-1352. Northern blot analysis of multiple human tissues showed that the TRAP240 gene is ubiquitously expressed as an approximately 11.5-kb transcript. Nagase et al. (1998) also cloned the cDNA encoding TRAP240, which they referred to as KIAA0593, from a human brain cDNA library.
Using several protein purification methods in HeLa cells, Sato et al. (2004) confirmed that MED13 (TRAP240) is a component of the Mediator complex.
By analysis of a human-rodent hybrid panel, Nagase et al. (1998) mapped the MED13 gene to chromosome 17.
Stumpf (2020) mapped the MED13 gene to chromosome 17q23.2 based on an alignment of the MED13 sequence (GenBank BC140891.1) with the genomic sequence (GRCh38).
In 11 unrelated patients and an affected mother-daughter duo with autosomal dominant intellectual developmental disorder-61 (MRD61; 618009), Snijders Blok et al. (2018) identified heterozygous mutations in the MED13 gene (see, e.g., 603808.0001-603808.0005). The patients were ascertained through collaborative research efforts and the GeneMatcher program. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The mutations occurred de novo in 11 patients; 1 was inherited from an affected mother. There were 3 nonsense, 2 frameshift, and 6 missense variants, and 1 in-frame deletion of a single residue. Analysis of cells derived from a patient carrying an R1400X mutation (603808.0004) showed normal levels of MED13 transcript and protein, with no detection of a truncated protein product. The mutant transcript was detected at about 70% level compared to wildtype. Additional functional studies of the other variants and of other patient cells were not performed. Snijders Blok et al. (2018) noted that mutations in other genes encoding subunits of the Mediator complex have been associated with neurodevelopmental disorders, which supports the hypothesis that MED13 variants may be responsible for this phenotype.
In a mother and daughter (patients B and C) with autosomal dominant intellectual developmental disorder-61 (MRD61; 618009), Snijders Blok et al. (2018) identified a heterozygous c.392T-G transversion (c.392T-G, NM_005112.2) in the MED13 gene, resulting in a leu131-to-ter (L131X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 19-year-old man (patient D) with autosomal dominant intellectual developmental disorder-61 (MRD61; 618009), Snijders Blok et al. (2018) identified a de novo heterozygous c.977C-T transition (977C-T, NM_005112.2) in the MED13 gene, resulting in a thr326-to-ile (T326I) substitution at a conserved residue in the N-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 6-year-old boy (patient I) with autosomal dominant intellectual developmental disorder-61 (MRD61; 618009), Snijders Blok et al. (2018) identified a de novo heterozygous c.1745T-A transversion (c.1745T-A, NM_005112.2) in the MED13 gene, resulting in a leu582-to-ter (L582X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 13-year-old girl (patient J) with autosomal dominant intellectual developmental disorder-61 (MRD61; 618009), Snijders Blok et al. (2018) identified a de novo heterozygous c.4198C-T transition (c.4198C-T, NM_005112.2) in the MED13 gene, resulting in an arg1400-to-ter (R1400X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Analysis of patient cells showed normal levels of MED13 transcript and protein, with no detection of a truncated protein product. The mutant transcript was detected at about a 70% level compared to wildtype.
In a 5-year-old boy (patient K) with autosomal dominant intellectual developmental disorder-61 (MRD61; 618009), Snijders Blok et al. (2018) identified a de novo heterozygous 1-bp deletion (c.4487delC, NM_005112.2) in the MED13 gene, resulting in a frameshift and premature termination (Thr1496Metfs). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
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]
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
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]
Snijders Blok, L., Hiatt, S. M. Bowling, K. M., Prokop, J. W., Engel, K. L., Cochran, J. N., Bebin, E. M., Bijlsma, E., Ruivenkamp, C. A. L., Terhal, P., Simon, M. E. H., Smith, R., and 20 others. De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder. Hum. Genet. 137: 375-388, 2018. [PubMed: 29740699] [Full Text: https://doi.org/10.1007/s00439-018-1887-y]
Stumpf, A. M. Personal Communication. Baltimore, Md. 02/04/2020.