Highlights
- •MED12 is potentially a candidate gene for X-linked recessive partial epilepsy without development/intellectual abnormalities.
- •MED12-related epilepsy is associated with MED12 missense variants in X-linked recessive inheritance.
- •The epilepsy-related variants of MED12 are located at the MED12-LCEWAV domain and the regions between MED12-LCEWAV and MED12-POL.
- •The phenotypes associated with MED12-related disorder exhibit a strong correlation with the specific variant types and in heritance patterns.
Abstract
Objectives
The MED12 gene encodes mediator complex subunit 12, which is a component of the mediator complex
involved in the transcriptional regulation of nearly all RNA polymerase II-dependent
genes. MED12 variants have previously been associated with developmental disorders with or without
nonspecific intellectual disability. This study aims to explore the association between
MED12 variants and epilepsy.
Materials and methods
Trios-based whole-exome sequencing was performed in a cohort of 349 unrelated cases
with partial (focal) epilepsy without acquired causes. The genotype-phenotype correlations
of MED12 variants were analyzed.
Results
Five hemizygous missense MED12 variants, including c.958A>G/p.Ile320Val, c.1757G>A/p.Ser586Asn, c.2138C>T/p.Pro713Leu, c.3379T>C/p.Ser1127Pro, and c.4219A>C/p.Met1407Leu
were identified in five unrelated males with partial epilepsy. All patients showed
infrequent focal seizures and achieved seizure free without developmental abnormalities
or intellectual disability. All the hemizygous variants were inherited from asymptomatic
mothers (consistent with the X-linked recessive inheritance pattern) and were absent
in the general population. The two variants with damaging hydrogen bonds were associated
with early-onset seizures. Further genotype-phenotype analysis revealed that congenital
anomaly disorder (Hardikar syndrome) was associated with (de novo) destructive variants
in an X-linked dominant inheritance pattern, whereas epilepsy was associated with
missense variants in an X-linked recessive inheritance pattern. Phenotypic features
of intellectual disability appeared as the intermediate phenotype in terms of both
genotype and inheritance. Epilepsy-related variants were located at the MED12-LCEWAV
domain and the regions between MED12-LCEWAV and MED12-POL.
Conclusion
MED12 is a potentially causative gene for X-linked recessive partial epilepsy without developmental
or intellectual abnormalities. The genotype-phenotype correlation of MED12 variants explains the phenotypic variations and can help the genetic diagnosis.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Seizure - European Journal of EpilepsyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Mediator is a transducer of Wnt/beta-catenin signaling.J Biol Chem. 2006; 281: 14066-14075
- The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with mediator.Genes Dev. 2013; 27: 151-156
- Molecular and in vivo functions of the CDK8 and CDK19 kinase modules.Front Cell Dev Biol. 2018; 6: 171
- A precisely positioned MED12 activation helix stimulates CDK8 kinase activity.Proc Natl Acad Sci U S A. 2020; 117: 2894-2905
- Med12 is essential for early mouse development and for canonical Wnt and Wnt/PCP signaling.Development. 2010; 137: 2723-2731
- Mutations in MED12 cause X-linked Ohdo syndrome.Am J Hum Genet. 2013; 92: 401-406
- The original Lujan syndrome family has a novel missense mutation (p. N1007S) in the MED12 gene.J Med Genet. 2007; 44: 472-477
- Blepharophimosis-mental retardation (BMR) syndromes: a proposed clinical classification of the so-called Ohdo syndrome, and delineation of two new BMR syndromes, one x-linked and one autosomal recessive.Am J Med Genet Part A. 2006; 140a: 1285-1296
- A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome.Nat Genet. 2007; 39: 451-453
- De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females.Genet Med. 2021; 23: 645-652
- MED12 related disorders.GeneReviews. 2021;
- The power of the mediator complex-expanding the genetic architecture and phenotypic spectrum of MED12-related disorders.Clin Genet. 2018; 94: 450-456
- Evaluating the pathogenic potential of genes with de novo variants in epileptic encephalopathies.Genet Med. 2019; 21: 17-27
- UNC13B variants associated with partial epilepsy with favourable outcome.Brain. 2021; 144: 3050-3060
- I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure.Nucleic Acids Res. 2005; 33: W306-W310
- Epilepsy-associated genes.Seizure-Eur J Epilepsy. 2017; 44: 11-20
- Evaluating the clinical validity of gene-disease associations: an evidence-based framework developed by the clinical genome resource.Am J Hum Genet. 2017; 100: 895-906
- Human mediator enhances basal transcription by facilitating recruitment of transcription factor IIB during preinitiation complex assembly.J Biol Chem. 2006; 281: 15172-15181
- The mediator complex: a master coordinator of transcription and cell lineage development.Development. 2014; 141: 977-987
- Malleable machines in transcription regulation: the mediator complex.PLoS Comput Biol. 2008; 4
- MED12-related (Neuro)developmental disorders: a question of causality.Genes (Basel). 2021; 12
- CDD/SPARCLE: the conserved domain database in 2020.Nucleic Acids Res. 2020; 48: D265-D268
- MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.Hum Mol Genet. 2017; 26: 2062-2075
- Med12 is essential for early mouse development and for canonical Wnt and Wnt/PCP signaling.Development. 2010; 137: 2723-2731
- X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.Mol Psychiatry. 2016; 21: 133-148
- Optimization of in silico tools for predicting genetic variants: individualizing for genes with molecular sub-regional stratification.Brief Bioinform. 2020; 21: 1776-1786
Article info
Publication history
Published online: February 26, 2023
Accepted:
February 23,
2023
Received in revised form:
February 21,
2023
Received:
January 19,
2023
Publication stage
In Press Journal Pre-ProofFootnotes
For the China Epilepsy Gene 1.0 Project
Identification
Copyright
© 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
