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MED25
mediator complex subunit 25
MED25 is located on the long (q) arm of chromosome 19, at band 19q13.33. Arm ratio per GRCh38 - banding schematic.
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Overview
MED25 (mediator complex subunit 25) encodes a component of the Mediator complex, a large multi-protein assembly that serves as a bridge between gene-activating proteins and the RNA polymerase II machinery that transcribes DNA into RNA. The gene is located on chromosome 19 and produces a 747-amino-acid protein that facilitates communication between transcription factors and the core transcription apparatus.
The MED25 protein is particularly important during embryonic development, where it helps coordinate the activation of genes in response to developmental signals. Pathogenic variants in MED25 have been associated with developmental disorders, and the gene appears on several NHS clinical panels related to developmental abnormalities and intellectual disability.
What the gene does
The MED25 protein functions as an adaptor within the Mediator complex, enabling communication between DNA-binding transcription factors and RNA polymerase II. The protein helps regulate gene expression by transmitting activating signals from sequence-specific transcription factors to the basal transcription machinery, effectively controlling how strongly particular genes are expressed in different cell types and developmental stages.
MED25 interacts with several important regulatory proteins, including nuclear hormone receptors such as the retinoic acid receptor (RARA), which coordinates developmental gene expression programmes. The protein also binds to transcriptional co-activators like CREBBP, which helps integrate multiple signalling pathways. Through these interactions, MED25 enables cells to respond appropriately to hormonal signals and developmental cues that guide tissue formation and cellular differentiation during embryonic development and throughout life.
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Chromosome location
MED25 is located on the long arm of chromosome 19 at position 19q13.33, a region near the telomere of the chromosome. The gene spans a genomic region that encodes the 747-amino-acid MED25 protein. Chromosome 19 is gene-dense and contains numerous genes involved in fundamental cellular processes and developmental regulation.
Protein structure
The MED25 protein displays a modular architecture with distinct functional regions spanning its 747 amino acids. The N-terminal portion (amino acids 1-226) mediates interaction with the Mediator complex itself, anchoring MED25 within the larger assembly. The protein contains multiple disordered regions (amino acids 233-274, 299-390, and 548-747), which provide flexibility that may facilitate interactions with multiple partner proteins.
The central and C-terminal portions of MED25 serve as interaction surfaces for transcriptional regulators. A region spanning amino acids 389-543 binds the VP16 activation domain, whilst overlapping sequences (amino acids 395-545) interact with CREBBP. Two distinct regions mediate interaction with RARA (amino acids 564-653 and 640-707), enabling the protein to respond to retinoic acid signalling. The protein also contains an LXXLL motif at amino acids 646-650, a signature sequence commonly found in proteins that interact with nuclear hormone receptors.
Key variants
Genetic variants in MED25 that disrupt protein function have been identified in individuals with developmental disorders. Pathogenic changes may interfere with the protein's ability to interact with the Mediator complex or with transcription factors, potentially disrupting gene expression programmes required for normal embryonic development. The specific effects of individual variants depend on their location within the protein and how they alter the encoded amino acid sequence.
Sample of pathogenic variants
3 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.418C>T | p.Arg140Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome |
c.781_791del | p.Pro261fs | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.116A>G | p.Tyr39Cys | Pathogenic | - | Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Alterations in MED25 have been associated with developmental disorders affecting multiple organ systems. Clinical features reported in individuals with MED25-related conditions may include cleft lip or palate, developmental delay, and intellectual disability. The range and severity of features can vary between affected individuals, reflecting the gene's role in coordinating developmental gene expression across different tissues. The inheritance patterns observed in MED25-related conditions may vary depending on the specific variant and clinical presentation.
No disease links recorded for this gene in our reference set.
UK clinical status
MED25 appears on several NHS Genomic Medicine Service gene panels that guide genetic testing in clinical practice. The gene holds green classification (high evidence for disease association) on the Clefting panel, the DDG2P panel (Developmental Disorders Genotype-to-Phenotype database), and the Intellectual disability panel (version R29). It also appears on the Fetal anomalies panel (version R21) with green classification, reflecting the gene's relevance to prenatal presentations of developmental disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the MED25 gene do?
MED25 encodes a subunit of the Mediator complex, which acts as a molecular bridge connecting gene-activating proteins to the cellular machinery that transcribes DNA into RNA. This protein helps control which genes are turned on and how strongly they are expressed, particularly during embryonic development.
How are conditions related to MED25 inherited?
The inheritance patterns for MED25-related conditions can vary depending on the specific variant and clinical presentation. Some variants may follow autosomal dominant inheritance (one altered copy sufficient to cause features), whilst others may require variants in both gene copies. Genetic counselling can help clarify inheritance patterns for individual families.
Is MED25 testing available through the NHS?
MED25 appears on several NHS gene panels including those for clefting, intellectual disability, and foetal anomalies. Testing availability depends on clinical presentation and would typically be coordinated through a clinical genetics service following referral by a specialist.