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dc.contributor.authorCalpena, E
dc.contributor.authorHervieu, A
dc.contributor.authorKaserer, T
dc.contributor.authorSwagemakers, SMA
dc.contributor.authorGoos, JAC
dc.contributor.authorPopoola, O
dc.contributor.authorOrtiz-Ruiz, MJ
dc.contributor.authorBarbaro-Dieber, T
dc.contributor.authorBownass, L
dc.contributor.authorBrilstra, EH
dc.contributor.authorBrimble, E
dc.contributor.authorFoulds, N
dc.contributor.authorGrebe, TA
dc.contributor.authorHarder, AVE
dc.contributor.authorLees, MM
dc.contributor.authorMonaghan, KG
dc.contributor.authorNewbury-Ecob, RA
dc.contributor.authorOng, K-R
dc.contributor.authorOsio, D
dc.contributor.authorReynoso Santos, FJ
dc.contributor.authorRuzhnikov, MRZ
dc.contributor.authorTelegrafi, A
dc.contributor.authorvan Binsbergen, E
dc.contributor.authorvan Dooren, MF
dc.contributor.authorDeciphering Developmental Disorders Study
dc.contributor.authorvan der Spek, PJ
dc.contributor.authorBlagg, J
dc.contributor.authorTwigg, SRF
dc.contributor.authorMathijssen, IMJ
dc.contributor.authorClarke, PA
dc.contributor.authorWilkie, AOM
dc.date.accessioned2019-11-01T10:34:20Z
dc.date.issued2019-04
dc.identifier.citationAmerican journal of human genetics, 2019, 104 (4), pp. 709 - 720
dc.identifier.issn0002-9297
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3399
dc.identifier.eissn1537-6605
dc.identifier.doi10.1016/j.ajhg.2019.02.006
dc.description.abstractThe 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.
dc.formatPrint-Electronic
dc.format.extent709 - 720
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectDeciphering Developmental Disorders Study
dc.subjectBrain
dc.subjectHumans
dc.subjectHeart Defects, Congenital
dc.subjectSyndrome
dc.subjectCyclin-Dependent Kinases
dc.subjectDevelopmental Disabilities
dc.subjectPhosphorylation
dc.subjectHeterozygote
dc.subjectPhenotype
dc.subjectMutation
dc.subjectMutation, Missense
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectInfant
dc.subjectFemale
dc.subjectMale
dc.subjectCyclin C
dc.subjectCyclin-Dependent Kinase 8
dc.subjectMediator Complex
dc.subjectIntellectual Disability
dc.subjectExome
dc.titleDe Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
dc.typeJournal Article
dcterms.dateAccepted2019-02-04
rioxxterms.versionofrecord10.1016/j.ajhg.2019.02.006
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAmerican journal of human genetics
pubs.issue4
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.publication-statusPublished
pubs.volume104
pubs.embargo.termsNo embargo
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
dc.contributor.icrauthorHervieu Vilches, Alexiaen
dc.contributor.icrauthorClarke, Paulen


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