MED13Developmental Delay and/or Intellectual Disability

(DD/ID)

Patients with MED13 variants having overlapping phenotypes.1

Conservation of site seen mutated in four different patients shown above.1

1. Snijders Blok L, Hiatt SM, Bowling KM, Prokop JW, Engel KL, Cochran JN, Bebin EM, Bijlsma EK, Ruivenkamp CAL, Terhal P, Simon MEH, Smith R, Hurst JA, DDD study, McLaughlin H, Person R, Crunk A, Wangler MF, Streff H, Symonds JD, Zuberi SM, Elliott KS, Sanders VR, Masunga A, Hopkin RJ, Dubbs HA, Ortiz-Gonzalez XR, Pfundt R, Brunner HG, Fisher SE, Kleefstra T, Cooper GM. De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder. Hum Genet. 2018 May;137(5):375–388. PMCID: PMC5973976

MED13Developmental Delay and/or Intellectual Disability

(DD/ID)MED13 is a component of the CDK8-kinase module that reversibly binds Mediator, a multi-

protein complex that is required for Polymerase II transcription initiation. The Mediator complex is essential for the expression of all protein-coding genes. Mutations in other genes encoding subunits of Mediator have previously been shown to be associated with DD/ID. The findings of this study add MED13 to the group of CDK8-kinase module associated disease genes.

The significance of a mutation in MED13 was identified through a GeneMatcher collaboration which identified a cohort of 13 individuals with protein-altering variants in MED13. 11 of the 13 variants were classified as de novo, the remaining two belonged to a mother and daughter. Every member of the cohort had an intellectual disability and/or developmental delays including speech delays and disorders. Other common phenotypes included autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. The phenotypic effects displayed led researchers to classify the variant in MED13 seen in each patient as likely pathogenic. This study showed that variants in MED13 are associated with neurodevelopmental disorders and delineated the corresponding phenotypic features and mutational spectrum.

The MED13 transcript encodes a large protein consisting of over 2,000 amino acids. Two domains within MED13 protein have been characterized, an N-terminal domain and a C-terminal domain. Conservation analysis of the protein indicated several highly conserved residues between these two domains. All variants found in the patients were predicted to be highly deleterious by CADD. Six individuals had mutations that were predicted to truncate the MED13 protein, six had missense mutations, and one individual had an in-frame-deletion of one amino acid. The seven non-truncating mutations clustered in two specific conserved locations in the MED13 protein – an N-terminal and C-terminal region. These seven variants were all found to be part of motifs that are highly conserved and to affect sites under high codon selection. They are all located on surface-exposed sites as shown on the three-dimensional model of the MED13 protein.

The four N-terminal mutations affect two adjacent amino acids that have been identified to be in involved in MED13 ubiquitination and degradation, p. Thr326 and p. Pro327 (3D model). They are required for binding with SCF-Fbw7 ubiquitin ligase for degradation. Using previous models of another protein with a similar Fbw7 interaction motif as MED13 all four variants were predicted to alter the phosphorylation and Fbw7 interaction.

Truncating mutations often lead to nonsense-mediated decay and haploinsufficiency, leading to loss-of-function. Patterns of variation in MED13 in human population databases indicate that MED13 is relatively intolerant to loss-of-function variation. It can be predicted then that the five truncating MED13 mutations would lead to a loss-of-function of the MED13 protein.

This study concluded that rare protein-altering variations in MED13 underlie a new neurodevelopmental disorder. This conclusion is supported by the results of the study including: a significant enrichment of de novo mutations in MED13 within ID/DD cohorts, the clustering and conservation levels of the positions affected by the observed missense variation, the computationally predicted deleteriousness of the observed mutations, and the overlap of phenotypic features among the cohort. Findings from other studies also indicate that MED13 could underlie a neurodevelopmental disorder including; evidence from other studies that identified MED13 variations in other families affected by neurodevelopmental disorders, the intolerance of MED13 to mutations, and the previously identified disease-associations of other Mediator subunits. The exact pathogenic mechanism of MED13 is yet to be identified. It has been found highly likely that mutational disruption of MED13 leads to disease. Because of this MED13 has been added to the list of Mediator-associated, specifically CDK8-kinase module associated, neurodevelopmental disorders.