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

Autor:	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., 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.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2019 Apr 04; Vol. 104 (4), pp. 709-720. Date of Electronic Publication: 2019 Mar 21.
DOI:	10.1016/j.ajhg.2019.02.006
Abstrakt:	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. (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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