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

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

In: American Journal of Human Genetics, Vol. 104, No. 4, 04.04.2019, p. 709-720.

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The Deciphering Developmental Disorders Study 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, vol. 104, no. 4, pp. 709-720. https://doi.org/10.1016/j.ajhg.2019.02.006

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The Deciphering Developmental Disorders Study. / De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 4. pp. 709-720.

Bibtex

@article{70a59186c2f94fe5b91566b0f2f64ea5,
title = "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder",
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.",
keywords = "behavioral disorder, CDK8, congenital heart disease, de novo mutation, dominant negative, hypotonia, intellectual disability, kinase, Mediator complex, Mediator kinase modulopathy",
author = "{The Deciphering Developmental Disorders Study} and Eduardo Calpena and Alexia Hervieu and Teresa Kaserer and Swagemakers, {Sigrid M.A.} and Goos, {Jacqueline A.C.} and Olajumoke Popoola and Ortiz-Ruiz, {Maria Jesus} and Tina Barbaro-Dieber and Lucy Bownass and Brilstra, {Eva H.} and Elise Brimble and Nicola Foulds and Grebe, {Theresa A.} and Harder, {Aster V.E.} and Lees, {Melissa M.} and Monaghan, {Kristin G.} and Newbury-Ecob, {Ruth A.} and Ong, {Kai Ren} and Deborah Osio and {Reynoso Santos}, {Francis Jeshira} and Ruzhnikov, {Maura R.Z.} and Aida Telegrafi and {van Binsbergen}, Ellen and {van Dooren}, {Marieke F.} and {van der Spek}, {Peter J.} and Julian Blagg and Twigg, {Stephen R.F.} and Mathijssen, {Irene M.J.} and Clarke, {Paul A.} and Wilkie, {Andrew O.M.}",
year = "2019",
month = "4",
day = "4",
doi = "10.1016/j.ajhg.2019.02.006",
language = "English",
volume = "104",
pages = "709--720",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder

AU - The Deciphering Developmental Disorders Study

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 - 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.

PY - 2019/4/4

Y1 - 2019/4/4

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.

AB - 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.

KW - behavioral disorder

KW - CDK8

KW - congenital heart disease

KW - de novo mutation

KW - dominant negative

KW - hypotonia

KW - intellectual disability

KW - kinase

KW - Mediator complex

KW - Mediator kinase modulopathy

UR - http://www.scopus.com/inward/record.url?scp=85063692095&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2019.02.006

DO - 10.1016/j.ajhg.2019.02.006

M3 - Article

C2 - 30905399

AN - SCOPUS:85063692095

VL - 104

SP - 709

EP - 720

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -