Skip to content

De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder

Research output: Contribution to journalArticle

  • The Deciphering Developmental Disorders Study
Original languageEnglish
Pages (from-to)709-720
Number of pages12
JournalAmerican Journal of Human Genetics
Volume104
Issue number4
Early online date21 Mar 2019
DOIs
DateAccepted/In press - 4 Feb 2019
DateE-pub ahead of print - 21 Mar 2019
DatePublished (current) - 4 Apr 2019

Abstract

The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.

    Research areas

  • behavioral disorder, CDK8, congenital heart disease, de novo mutation, dominant negative, hypotonia, intellectual disability, kinase, Mediator complex, Mediator kinase modulopathy

Download statistics

No data available

Documents

Documents

  • Full-text PDF (final published version)

    Rights statement: This is the final published version of the article (version of record). It first appeared online via Elsevier at https://doi.org/10.1016/j.ajhg.2019.02.006 . Please refer to any applicable terms of use of the publisher.

    Final published version, 2 MB, PDF document

    Licence: CC BY

DOI

View research connections

Related faculties, schools or groups