Alternative titles; symbols
HGNC Approved Gene Symbol: MED12
SNOMEDCT: 422437002, 49984004, 699297004, 720636001;
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38) : X:71,118,596-71,142,450 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq13.1 | Hardikar syndrome | 301068 | X-linked dominant | 3 |
| Lujan-Fryns syndrome | 309520 | X-linked recessive | 3 | |
| Ohdo syndrome, X-linked | 300895 | X-linked recessive | 3 | |
| Opitz-Kaveggia syndrome | 305450 | X-linked recessive | 3 |
Mediator is a multiprotein complex that can function in transcriptional activation or repression depending on the factors with which it interacts. The Mediator subunit MED12 has roles in both transcriptional activation and repression (Ding et al., 2008).
Nagase et al. (1996) cloned a cDNA, which they referred to as KIAA0192, from the human cell line KG-1. They found that the cDNA contains stretches of CAG (gln) repeats and encodes a 2,124-amino acid protein.
Using a HeLa cell line, Ito et al. (1999) cloned the same gene, TRAP230, which encodes the 230-kD subunit of the thyroid hormone receptor-associated protein (TRAP) complex (see 300182). The sequence of the TRAP230 protein was found in 2 other reports of partial sequences: CAG H45 (Margolis et al., 1997), and an opposite paired (OPA)-containing protein called HOPA by Philibert et al. (1998) located on chromosome Xq13. TRAP230 also contains 2 overlapping ligand-dependent nuclear hormone receptor signature recognition motifs (LxxLL motifs) near the N terminus and a highly glutamine-rich C-terminal region that results from the CAG trinucleotide repeats. Sequence comparisons revealed that TRAP230 also has significant homology with a hypothetical C. elegans protein (CEF47A4). This protein has a regional identity of 23% and similarity of 40% with TRAP230 and also possesses a characteristic glutamine-rich sequence near the C terminus. Northern blot analysis of multiple human tissues showed that the TRAP230 gene is ubiquitously expressed as an approximately 7.6-kb transcript.
By Northern blot analysis of the HOPA gene transcript and its murine ortholog, Mopa1, Philibert et al. (1999) demonstrated that only 1 transcript is expressed throughout the central nervous system and other tissues, and that the transcript is highly expressed during early fetal development. The presence of an OPA (opposite paired) element strongly suggested that HOPA is under tissue- or developmental-specific control (Grabowski et al., 1991).
Philibert et al. (1999) sequenced the HOPA gene and found that spans 25 kb and contains 44 exons. A promoter scan analysis demonstrated 2 possible transcription initiation sites without TATA boxes upstream from the putative translation initiation start site.
Risheg et al. (2007) stated that the MED12 gene contains 45 exons.
By use of human/rodent hybrid cell lines, Nagase et al. (1996) mapped the MED12 gene to the X chromosome.
By yeast 2-hybrid analysis of a human embryo cDNA expression library, Zhou et al. (2002) found that the transcription activation domain of SOX9 (608160) interacted with the proline-, glutamine-, and leucine-rich (PQL) domain of TRAP230. In vitro and in vivo assays confirmed that the proteins interact endogenously and associate with several other TRAP complex proteins in HeLa cell nuclear lysates. SOX9 and TRAP230 colocalized in nuclei of cultured human embryo chondrocytes. The isolated PQL domain of TRAP230 acted as a dominant-negative inhibitor of SOX9 activity.
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 (603810) 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, 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.
Ding et al. (2008) showed that MED12 was required for transcriptional repression of a subset of neuron-specific genes in human nonneuronal cell lines, and that this repression was independent of CDK8 and CYCC. Yeast 2-hybrid analysis showed that the C-terminal domain of MED12 interacted directly with the H3K9 histone methyltransferase G9A (EHMT2; 604599). Mutation analysis revealed that the pro-glu-leu (PQL) domain of MED12 interacted with an ankyrin-repeat domain on G9A and, more weakly, with a cys-rich domain on G9A. Purified HeLa cell Mediator complexes that included MED12 interacted directly with G9A and REST (600571), a gene repressor that functions through repressor element-1 (RE1). Endogenous REST in HEK293 cells suppressed expression of a reporter gene bearing RE1 sites, and knockdown of either MED12 or G9A abrogated the suppression. Depletion of MED12 significantly reduced the association of G9A with RE1 elements and decreased the level of H3K9 dimethylation by G9A without influencing RE1 site occupancy by REST. Both the MED12 arg961-to-trp (R961W; 300188.0001) mutation associated with Opitz-Kaveggia syndrome (305450) and the MED12 asn1007-to-ser (N1007S; 300188.0002) mutation associated with Lujan-Fryns syndrome (309520) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST target genes. Ding et al. (2008) concluded that MED12 within the Mediator complex links REST with G9A in epigenetic silencing of neuronal genes.
A class of long noncoding RNAs (lncRNAs) termed noncoding RNA-activating (ncRNA-a) functions to activate their neighboring genes using a cis-mediated mechanism. Lai et al. (2013) reported that the depletion of the components of the coactivator complex, Mediator, specifically and potently diminished the noncoding RNA-induced activation of transcription in a heterologous reporter assay using human HEK293 cells. In vivo, Mediator is recruited to ncRNA-a target genes and regulates their expression. Lai et al. (2013) showed that ncRNA-a interact with Mediator to regulate its chromatin localization and kinase activity towards histone H3 serine-10. The Mediator complex harboring disease-causing MED12 mutations displayed diminished ability to associate with activating ncRNAs. Chromosome conformation capture confirmed the presence of DNA looping between the ncRNA-a loci and its targets. Importantly, depletion of Mediator subunits or ncRNA-a reduced the chromatin looping between the 2 loci. Lai et al. (2013) concluded that their results identified the human Mediator complex as the transducer of activating ncRNAs and highlighted the importance of Mediator and activating ncRNA association in human disease.
Opitz-Kaveggia Syndrome
Opitz-Kaveggia syndrome (305450), also known as FG syndrome, is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia, and constipation. Risheg et al. (2007) reported that the original family from which the designation FG was derived and 5 other families had a recurrent mutation in the MED12 gene, 2881C-T (R961W; 300188.0001). MED12 was considered a candidate gene because of its mapping to Xq13 and because it encodes a thyroid hormone receptor-associated protein (TRAP). Risheg et al. (2007) sequenced the 45 exons of MED12 in 24 index cases from XLMR families with linkage to Xq13. Two of the 24 index cases had the identical R961W missense mutation. In both of these individuals, the diagnosis of Opitz-Kaveggia syndrome had been made a priori. In all affected males who survived long enough for mental or cognitive assessment, mental retardation was present. Partial or complete absence of the corpus callosum was noted in all 6 cases in which brain imaging was available. High, prominent forehead and small, low-set, simple ears were the most consistent craniofacial manifestations. Imperforate anus, wide flat thumbs, and wide great toes were present in 7 of 10 cases. Cryptorchidism, inguinal hernia, cardiac defects, and short stature were noted in fewer than half of affected males. Risheg et al. (2007) proposed that the Opitz-Kaveggia syndrome designation be reserved for those individuals with MED12 mutations.
Intellectual Developmental Disorder, X-linked, Syndromic, Lujan-Fryns Type
In 4 affected members of a family with Lujan-Fryns syndrome (MRXSLF; 309520) originally reported by Lujan et al. (1984), Schwartz et al. (2007) identified a mutation in the MED12 gene (300188.0002). The same mutation was found in affected members of an unrelated family. The findings indicated that Lujan-Fryns syndrome and Opitz-Kaveggia syndrome are allelic disorders. Clinically, Lujan-Fryns syndrome could be distinguished by tall stature, hypernasal voice, hyperextensible digits, and high nasal root. Schwartz et al. (2007) suggested that the Lujan-Fryns syndrome designation be used only for those cases with a compatible clinical phenotype and mutations in the MED12 gene.
Ohdo Syndrome, X-Linked
Vulto-van Silfhout et al. (2013) performed exome sequencing in 2 families segregating X-linked Ohdo syndrome (OHDOX; 300895), including the family originally studied by Maat-Kievit et al. (1993) and another family with 2 affected males, and identified hemizygous missense mutations in the MED12 gene (R1148H, 300188.0003 and S1165P, 300188.0004) that segregated with the disorder in each family. By analysis of an additional cohort of 9 simplex male patients with Ohdo syndrome, they identified another MED12 missense mutation (H1729N; 300188.0005) in 1 patient.
Vulto-van Silfhout et al. (2013) comparatively examined siRNA-resistant wildtype FLAG-tagged MED12 (FLAG-MED12) and its corresponding R1148H and S1165P mutant derivatives for their respective abilities to suppress enhanced REST target gene expression triggered by RNAi-mediated depletion of endogenous MED12 in HEK293 cells. MED12 knockdown triggered derepression of REST target genes, including CHRM4 (118495), SNAP25 (600322), and SYN1 (313440). Introduction of wildtype FLAG-MED12 in these cells reversed this effect; in contrast, the R1148H and S1165P mutants were significantly compromised in this ability. Vulto-van Silfhout et al. (2013) also showed that neither amino acid change deleteriously affected the incorporation of MED12 into Mediator or its direct interaction with G9A, indicating that the MED12 mutations in Ohdo syndrome do not disrupt the function of MED12 as a stable G9A interface in Mediator.
In 3 brothers of Moldavian descent with Ohdo syndrome, Rubin et al. (2020) identified a hemizygous mutation in the MED12 gene (Q2159P; 300188.0006). The mutation was identified by whole-exome sequencing. The unaffected mother was heterozygous for the mutation. Functional studies were not performed.
Hardikar Syndrome
In 7 unrelated females with Hardikar syndrome (HDKR; 301068), Li et al. (2021) identified heterozygous nonsense or frameshift mutations in the MED12 gene (see, e.g., 300188.0007-300188.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred throughout the gene. All were predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. All of the mutations either occurred de novo or were presumed de novo. Functional studies of the variants were not performed. Patient cells showed skewed X inactivation. Li et al. (2021) postulated that complete loss of MED12 may be lethal in males. The authors noted that the HDKR phenotype is unique in that neurodevelopment is preserved and that the manifestations include distinct structural abnormalities affecting several organ systems.
Associations Pending Confirmation
Susceptibility to Impaired Intellectual Development
Philibert et al. (1998) reported a strong association of a variant polymorphism, a 12-bp duplication (CAGCAACACCAG), in the HOPA gene with an X-linked mental retardation/hypothyroidism syndrome in several independent cohorts.
Friez et al. (2000) concluded that the 12-bp duplication in the HOPA gene is not associated with mental retardation. They determined the incidence of the dodecamer duplication in cohorts of non-fragile X males with mental retardation from 3 countries, cohorts of fragile X males from 2 countries, 43 probands from families with X-linked mental retardation, and control cohorts from 3 countries. The duplication was found in 3.6 to 4.0% of male patients from 2 non-fragile X groups, in 1.2% from another non-fragile X group, but in no male patients from families with X-linked mental retardation. The dodecamer duplication was also found in several white males with fragile X syndrome from France (5%) and South Africa (22.2%). Additionally, the duplication was found in 1.5% of South Carolinian newborn males, 2.5% of South Carolinian male college students, 5% of Italian male controls, and 4.5% of white South African controls. The duplication appeared to be rare in the black South African population. The incidence of the duplication was not significantly different between any of the groups in the study.
A study by Beyer et al. (2002) also failed to sustain the hypothesis that the HOPA gene is a significant susceptibility factor for infantile autism and mental retardation. The 12-bp duplication in the HOPA gene appeared to function as a benign polymorphism.
Uterine Leiomyoma
Makinen et al. (2011) performed whole-exome sequencing on 18 uterine leiomyomas derived from 17 different patients and identified tumor-specific mutations in the MED12 gene in 10. Analysis of 207 additional tumors identified MED12 mutations in 70% (159/225) of tumors from a total of 80 patients. The Mediator complex is a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex. All mutations identified by Makinen et al. (2011) resided in exon 2, suggesting that aberrant function of this region of MED12 contributes to tumorigenesis.
Prostate Cancer
Barbieri et al. (2012) sequenced the exomes of 112 prostate tumor (see 176807) and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1 (602294). SPOP (602650) was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6 to 15% of tumors across multiple independent cohorts. Prostate tumors with mutant SPOP lacked ETS family (see 164720) gene rearrangements and showed a distinct pattern of genomic alterations. Barbieri et al. (2012) concluded that SPOP mutations may define a novel molecular subtype of prostate cancer.
Hong et al. (2005) showed that med12-deficient zebrafish embryos showed defects in brain, neural crest, and kidney development and do not survive beyond 1 week after fertilization. Rau et al. (2006) showed, also in zebrafish, that med12 is required as a coactivator of Sox9 (608160)-dependent neural crest, cartilage, and ear development. Mutations in med12 are responsible for the zebrafish mutant 'motionless' (mot), and med12 transcripts are enriched in brain, where the gene is responsible for regulating the expression of other neuronal determination genes (Wang et al., 2006). These and other studies suggested that a variety of signaling pathways interact with MED12.
In the original family with what was designated the FG syndrome (305450) after the family initials, Risheg et al. (2007) found a 2881C-T transition in exon 21 of the MED12 gene that caused an arg961-to-trp amino acid substitution (R961W). They also found the same mutation in 5 other families. Failure to find the change in 451 normal men and in 343 consecutive newborn males suggested that it is not a rare polymorphic variant. The finding of the mutation in patients of various ethnic backgrounds suggested that families did not share a common ancestor.
Ding et al. (2008) showed that both the R961W mutation associated with Opitz-Kaveggia syndrome and the MED12 asn1007-to-ser (N1007S; 300188.0002) mutation associated with Lujan-Fryns syndrome (309520) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST (600571) target genes. The authors noted that these mutations do not alter the ability of MED12 to support beta-catenin (see CTNNB1; 116806) transactivation.
In 4 affected members of a family with Lujan-Fryns syndrome (MRXSLF; 309520) originally reported by Lujan et al. (1984), Schwartz et al. (2007) identified a 3020A-G transition in exon 22 of the MED12 gene, resulting in an asn1007-to-ser (N1007S) substitution. Affected members of an unrelated family carried the same mutation.
Ding et al. (2008) showed that both the N1007S mutation associated with Lujan-Fryns syndrome and the MED12 arg961-to-trp (R961W; 300188.0001) mutation associated with Opitz-Kaveggia syndrome (305450) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST (600571) target genes. The authors noted that these mutations do not alter the ability of MED12 to support beta-catenin (see CTNNB1; 116806) transactivation.
By exome sequencing in a family in which 2 males had Ohdo syndrome (OHDOX; 300895), originally described by Maat-Kievit et al. (1993) and Verloes et al. (2006), Vulto-van Silfhout et al. (2013) identified a hemizygous c.3443G-A transition in the MED12 gene, resulting in an arg1148-to-his (R1148H) substitution, that segregated with the phenotype. Arg1148 is a highly conserved residue, and the mutation was predicted to be damaging to protein function.
By exome sequencing in a family in which 2 males had Ohdo syndrome (OHDOX; 300895), Vulto-van Silfhout et al. (2013) identified a hemizygous c.3493T-C transition in the MED12 gene, resulting in a ser1165-to-pro (S1165P) substitution, that segregated with the phenotype. Ser1165 is a highly conserved residue, and the mutation was predicted to be damaging to protein function.
Vulto-van Silfhout et al. (2013) sequenced the MED12 in a cohort of 9 simplex male individuals with Ohdo syndrome (OHDOX; 300895) and identified a hemizygous de novo c.5185C-A transversion, resulting in a his1729-to-asn (H1729N) substitution in the PQL domain. His1729 is a highly conserved residue, and the mutation was predicted to be damaging to protein function.
In 3 Moldavian brothers with Ohdo syndrome (OHDOX; 300895), Rubin et al. (2020) identified a hemizygous c.6476A-C transversion in exon 44 of the MED12 gene, resulting in a gln2159-to-pro (Q2159P) substitution at a highly conserved location within the OPA (glutamine-rich) domain. The mutation was identified by whole-exome sequencing. The unaffected mother was heterozygous for the mutation. Functional studies were not performed.
In a 14-year-old girl (patient 4) with Hardikar syndrome (HDKR; 301068), Li et al. (2021) identified a presumed de novo heterozygous del/ins (c.4903_4906delinsCCAGCA) in the MED12 gene, predicted to result in a frameshift and premature termination (Val1635ProfsTer61). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. Functional studies of the variant were not performed. Patient cells showed skewed X inactivation (97:3). The patient had previously been reported by Poley and Proud (2008) and Ryan et al. (2016).
In a 21-year-old woman (patient 5) with Hardikar syndrome (HDKR; 301068), Li et al. (2021) identified a presumed de novo heterozygous c.5111G-A transition in the MED12 gene, predicted to result in a trp1704-to-ter (W1704X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. Functional studies of the variant were not performed. Patient cells showed skewed X inactivation (99:1). The patient died at age 21 years from an intracranial hemorrhage. The patient had previously been reported by Cools and Jaeken (1997).
In a 4-year-old girl (patient 6) with Hardikar syndrome (HDKR; 301068), Li et al. (2021) identified a de novo heterozygous c.5622C-A transversion in the MED12 gene, resulting in a tyr1874-to-ter (Y1874X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. Functional studies of the variant were not performed. Patient cells showed skewed X inactivation (97:3).
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