MED23

protein-coding

mediator complex subunit 23, the group of Mediator complex

Gene summary

The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. This protein also acts as a metastasis suppressor. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2012]

Previous symbols:

CRSP3
MRT18

MANE transcript

NM_004830.4

Inheritance

ClinVar variants

P:29U:171B:45

Top phenotype

Intellectual developmental disorder, autosomal recessive 18, with or without epilepsy

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr6:131,573,966-131,628,242

External References & Databases

Ensembl (ENSG00000112282)

Transcript & Mutation Effects

hg38 • Region Span ~54.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability, autosomal recessive 18LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013651

Submitter: G2P

intellectual disability, autosomal recessive 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013651

Submitter: PanelApp Australia

intellectual disability, autosomal recessive 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013651

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

syndromic intellectual disabilityMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0000508

Submitter: ClinGen

*MED23* is located on chromosome 6q23.2 and encodes a component of the Mediator complex, a regulator of RNA polymerase II transcription. *MED23* was first reported in relation to autosomal recessive non-syndromic intellectual disability in 2011 (Hashimoto et al., PMID 21868677). Although *MED23* was initially associated with non-syndromic intellectual disability, as more cases have been reported in the literature, a frequent phenotypic profile has emerged that includes global developmental delay, intellectual disability, early-onset epilepsy, axial hypotonia, spasticity, and microcephaly. Other features include delayed myelination or hypomyelination, thin corpus callosum, cerebral palsy, and movement disorders such as dystonia and choreoathetosis. For this reason, we selected syndromic intellectual disability as the disease entity for this curation. Twelve variants (1 nonsense, 10 missense, and 1 splice region) that have been reported in 9 probands in 9 publications (PMIDs: 21868677, 25845469, 27311965, 27457812, 30847200, 31164858, 36824420, 36990084, 39144687) are included in this curation. However, most of the reported variants are missense without supporting functional data. Only 3 families have variants with functional evidence of gene impact. Variants in this gene segregate with disease in 8 additional family members, including one family with 5 affected siblings (PMID: 21868677). The mechanism of pathogenicity appears to be loss of function. Variants in *MED23* and other mediator complex subunits are linked to neurological disorders through transcriptional dysregulation of target genes (PMID: 21868677). *MED23* variants were shown to disrupt the ability of MED23 to interact with transcription factors, leading to dysregulation of the expression of immediate early genes *JUN* and *FOS* in patient cells (PMIDs: 21868677, 25845469). This gene-disease relationship is also supported by experimental evidence, including biochemical function, protein interaction, a mouse model (PMID: 36718943), and rescue experiments (PMID: 21868677). Variants in other genes encoding subunits of the Mediator complex (*MED11*, *MED12*, *MED12L*, *MED13*, *MED13L*, *MED16*, *MED17*, *MED23*, *MED25*, *MED27*, *CDK8*, and *CDK19*) have been shown to be involved in neurodevelopmental disorders with overlapping features (PMID: 41465117). In summary, there is moderate evidence to support the relationship between *MED23* and autosomal recessive syndromic intellectual disability. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. Given that only 3 families with *MED23* variants supported by functional studies have been reported since the original study in 2011, additional genetic and experimental evidence is necessary to strengthen this gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 1, 2020. It was reevaluated on September 7, 2026 (SOP Version 12). As a result of this reevaluation, three additional patients were identified, but none had functional evidence of pathogenicity, and the classification did not change.

intellectual disability, autosomal recessive 18MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013651

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 18, with or without epilepsyAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: As with other forms of epilepsy, optimal seizure control is advantageous, and genetic diagnosis may aid with medication selection (eg, ketogenic diet has been described as beneficial)

Refs: 21868677; 27311965; 27457812; 30847200; 31164858

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MED23 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 150

not providedTotal: 79

Intellectual disability, autosomal recessive 18Total: 41

not specifiedTotal: 27

MED23-related disorderTotal: 12

Intellectual disabilityTotal: 2

Neurodevelopmental disorderTotal: 1

Fraser syndrome 3Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004830.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	43 clinvar	1 clinvar	47
missense	6 clinvar	5 clinvar	156 clinvar	1 clinvar		168
nonsense	1 clinvar	7 clinvar	2 clinvar			10
start loss						0
frameshift	2 clinvar	5 clinvar	3 clinvar			10
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	7 clinvar			10
Total	10	19	171	44	1	245

Highest pathogenic variant AF is 0.000041510488

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004830.4	RefSeq	NP_004821.2	29	MANE Select
ENST00000368068.8	Ensembl	ENSP00000357047.3	29	MANE Select
NM_001270521.2	RefSeq	NP_001257450.1	30	Standard
NM_001270522.2	RefSeq	NP_001257451.1	30	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
med23	Danio rerio	Structure: melanocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

med23

Danio rerio

Structure: melanocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

WNT-Ncore
Developmental Biology
Gene expression (Transcription)
Generic Transcription Pathway
Hedgehog

Biological Process

regulation of transcription, DNA-templated
regulation of transcription by RNA polymerase II
transcription initiation from RNA polymerase II promoter
positive regulation of nucleic acid-templated transcription

Molecular Function

transcription coactivator activity
protein binding

Cellular Component

nucleoplasm
transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368068
Coding exons: 29
Length: 54264
Individuals with no LoFs: 125665
Homozygous LoFs: 0
Heterozygous LoFs: 83
Defined: 125748
p: 0.000330

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.73	369	728	0.507	0.0000371	9047
Missense (PolyPhen)		144	368.6	0.39067		4718
Synonymous	1.21	232	257	0.904	0.0000132	2589
Loss of Function	5.09	27	74.4	0.363	0.00000404	862

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00044	0.00044	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00035	0.00035	rare
South Asian	0.00046	0.00046	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for transcriptional activation subsequent to the assembly of the pre-initiation complex (By similarity). Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Required for transcriptional activation by adenovirus E1A protein. Required for ELK1-dependent transcriptional activation in response to activated Ras signaling. {ECO:0000250, ECO:0000269|PubMed:10353252, ECO:0000269|PubMed:14759369, ECO:0000269|PubMed:16595664}.;
Disease: DISEASE: Mental retardation, autosomal recessive 18 (MRT18) [MIM:614249]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21868677}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.154

Intolerance Scores

LoFtool: 0.412
RVIS EVS: -1.13
RVIS percentile EVS: 6.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.932

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium