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De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
Am J Hum Genet. 2019 04 04; 104(4):709-720.AJ

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.

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Authors+Show Affiliations

Calpena E
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Hervieu A
Cancer Research UK Cancer Therapeutics Unit, the Institute of Cancer Research, London SM2 5NG, UK.
Kaserer T
Cancer Research UK Cancer Therapeutics Unit, the Institute of Cancer Research, London SM2 5NG, UK.
Swagemakers SMA
Department of Pathology and Department of Bioinformatics, Erasmus University Medical Center, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
Goos JAC
Department of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
Popoola O
Cancer Research UK Cancer Therapeutics Unit, the Institute of Cancer Research, London SM2 5NG, UK.
Ortiz-Ruiz MJ
Cancer Research UK Cancer Therapeutics Unit, the Institute of Cancer Research, London SM2 5NG, UK.
Barbaro-Dieber T
Genetics Division, Cook Children's Medical Center, Fort Worth, TX 76102, USA.
Bownass L
Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, St. Michael's Hospital, Bristol BS2 8EG, UK.
Brilstra EH
Department of Genetics, University Medical Center Utrecht, Utrecht University, 3508 AB Utrecht, the Netherlands.
Brimble E
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Foulds N
Wessex Clinical Genetics Services, University Hospital Southampton, Southampton SO16 5YA, UK.
Grebe TA
Department of Child Health, University of Arizona College of Medicine, Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
Harder AVE
Department of Genetics, University Medical Center Utrecht, Utrecht University, 3508 AB Utrecht, the Netherlands.
Lees MM
North Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3EH, UK.
Monaghan KG
GeneDx, Gaithersburg, MD 20877, USA.
Newbury-Ecob RA
Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, St. Michael's Hospital, Bristol BS2 8EG, UK.
Ong KR
Department of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.
Osio D
Department of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.
Reynoso Santos FJ
Genetics Division, Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA; Charles E. Schmidt College of Medicine, Florida Atlantic University, Hollywood, FL 33021, USA.
Ruzhnikov MRZ
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Telegrafi A
GeneDx, Gaithersburg, MD 20877, USA.
van Binsbergen E
Department of Genetics, University Medical Center Utrecht, Utrecht University, 3508 AB Utrecht, the Netherlands.
van Dooren MF
Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
Deciphering Developmental Disorders Study
Deciphering Developmental Disorders Study, Wellcome Sanger Institute, Cambridge CB10 1SA, UK.
van der Spek PJ
Department of Pathology and Department of Bioinformatics, Erasmus University Medical Center, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
Blagg J
Cancer Research UK Cancer Therapeutics Unit, the Institute of Cancer Research, London SM2 5NG, UK.
Twigg SRF
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Mathijssen IMJ
Department of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
Clarke PA
Cancer Research UK Cancer Therapeutics Unit, the Institute of Cancer Research, London SM2 5NG, UK. Electronic address: paul.clarke@icr.ac.uk.
Wilkie AOM
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. Electronic address: andrew.wilkie@imm.ox.ac.uk.

MeSH

BrainChildChild, PreschoolCyclin CCyclin-Dependent Kinase 8Cyclin-Dependent KinasesDevelopmental DisabilitiesExomeFemaleHeart Defects, CongenitalHeterozygoteHumansInfantIntellectual DisabilityMaleMediator ComplexMutationMutation, MissensePhenotypePhosphorylationSyndrome

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30905399

Citation

Calpena, Eduardo, et al. "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder." American Journal of Human Genetics, vol. 104, no. 4, 2019, pp. 709-720.
Calpena E, Hervieu A, Kaserer T, et al. De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. Am J Hum Genet. 2019;104(4):709-720.
Calpena, E., Hervieu, A., Kaserer, T., Swagemakers, S. M. A., Goos, J. A. C., Popoola, O., Ortiz-Ruiz, M. J., Barbaro-Dieber, T., Bownass, L., Brilstra, E. H., Brimble, E., Foulds, N., Grebe, T. A., Harder, A. V. E., Lees, M. M., Monaghan, K. G., Newbury-Ecob, R. A., Ong, K. R., Osio, D., ... Wilkie, A. O. M. (2019). De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. American Journal of Human Genetics, 104(4), 709-720. https://doi.org/10.1016/j.ajhg.2019.02.006
Calpena E, et al. De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. Am J Hum Genet. 2019 04 4;104(4):709-720. PubMed PMID: 30905399.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. AU - Calpena,Eduardo, AU - Hervieu,Alexia, AU - Kaserer,Teresa, AU - Swagemakers,Sigrid M A, AU - Goos,Jacqueline A C, AU - Popoola,Olajumoke, AU - Ortiz-Ruiz,Maria Jesus, AU - Barbaro-Dieber,Tina, AU - Bownass,Lucy, AU - Brilstra,Eva H, AU - Brimble,Elise, AU - Foulds,Nicola, AU - Grebe,Theresa A, AU - Harder,Aster V E, AU - Lees,Melissa M, AU - Monaghan,Kristin G, AU - Newbury-Ecob,Ruth A, AU - Ong,Kai-Ren, AU - Osio,Deborah, AU - Reynoso Santos,Francis Jeshira, AU - Ruzhnikov,Maura R Z, AU - Telegrafi,Aida, AU - van Binsbergen,Ellen, AU - van Dooren,Marieke F, AU - ,, AU - van der Spek,Peter J, AU - Blagg,Julian, AU - Twigg,Stephen R F, AU - Mathijssen,Irene M J, AU - Clarke,Paul A, AU - Wilkie,Andrew O M, Y1 - 2019/03/21/ PY - 2018/12/07/received PY - 2019/02/04/accepted PY - 2019/3/25/pubmed PY - 2020/2/6/medline PY - 2019/3/26/entrez KW - CDK8 KW - Mediator complex KW - Mediator kinase modulopathy KW - behavioral disorder KW - congenital heart disease KW - de novo mutation KW - dominant negative KW - hypotonia KW - intellectual disability KW - kinase SP - 709 EP - 720 JF - American journal of human genetics JO - Am J Hum Genet VL - 104 IS - 4 N2 - 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. SN - 1537-6605 UR - https://www.unboundmedicine.com/medline/citation/30905399/De_Novo_Missense_Substitutions_in_the_Gene_Encoding_CDK8_a_Regulator_of_the_Mediator_Complex_Cause_a_Syndromic_Developmental_Disorder_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(19)30051-5 DB - PRIME DP - Unbound Medicine ER -