De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
View/ Open
Date
2019-04-04Author
Calpena, E
Hervieu, A
Kaserer, T
Swagemakers, SMA
Goos, JAC
Popoola, O
Ortiz-Ruiz, MJ
Barbaro-Dieber, T
Bownass, L
Brilstra, EH
Brimble, E
Foulds, N
Grebe, TA
Harder, AVE
Lees, MM
Monaghan, KG
Newbury-Ecob, RA
Ong, K-R
Osio, D
Reynoso Santos, FJ
Ruzhnikov, MRZ
Telegrafi, A
van Binsbergen, E
van Dooren, MF
Deciphering Developmental Disorders Study,
van der Spek, PJ
Blagg, J
Twigg, SRF
Mathijssen, IMJ
Clarke, PA
Wilkie, AOM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Deciphering Developmental Disorders Study
Brain
Humans
Heart Defects, Congenital
Syndrome
Cyclin-Dependent Kinases
Developmental Disabilities
Phosphorylation
Heterozygote
Phenotype
Mutation
Mutation, Missense
Child
Child, Preschool
Infant
Female
Male
Cyclin C
Cyclin-Dependent Kinase 8
Mediator Complex
Intellectual Disability
Exome
Research team
Signal Transduction & Molecular Pharmacology
Language
eng
Date accepted
2019-02-04
License start date
2019-04
Citation
American journal of human genetics, 2019, 104 (4), pp. 709 - 720
Publisher
CELL PRESS