ArticleScientific reports2020
Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 20 citations in OpenAlex.
- Heterozygous Med13l mice recapitulate a developmental growth delay and craniofacial anomalies seen in MED13L syndrome.Developmental dynamics : an official publication of the American Association of Anatomists · 2026Article
- Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.Human molecular genetics · 2026Article
- Novel biallelic CDK9 variants are associated with retinal dystrophy without CHARGE-like malformation syndrome.Journal of human genetics · 2026Article
- let-7c-5p promotes fracture healing by downregulating CDK8.Journal of orthopaedic surgery and research · 2026Article
- Review
- The role of CDK8 gene polymorphisms in bladder cancer susceptibility and prognosis: a study in the Chinese Han population.BMC cancer · 2025Article
- Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.Nature communications · 2024Article
- Genetically Engineered Mice Unveil In Vivo Roles of the Mediator Complex.International journal of molecular sciences · 2023Review
- Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction iniScience · 2022Article
- Transcription Pause and Escape in Neurodevelopmental Disorders.Frontiers in neuroscience · 2022Review
- Association betweenCardiovascular diagnosis and therapy · 2021Article
- Recurrent NFIA K125E substitution represents a loss-of-function allele: Sensitive in vitro and in vivo assays for nontruncating alleles.American journal of medical genetics. Part A · 2021Article
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9 authors at 6 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Cyclin-dependent kinase 8 (CDK8) is a member of the CDK/Cyclin module of the mediator complex. A recent study reported that heterozygous missense CDK8 mutations cause a neurodevelopmental disorder in humans. The mechanistic basis of CDK8-related disorder has yet to be delineated. Here, we report 2 patients with de novo missense mutations within the kinase domain of CDK8 along with the results of in vitro and in vivo functional analyses using a zebrafish model. Patient 1 and Patient 2 had intellectual disabilities and congenital anomalies. Exome analyses showed that patient 1 had a heterozygous de novo missense p.G28A variant in the CDK8 (NM_001260.3) gene and patient 2 had a heterozygous de novo missense p.N156S variant in the CDK8 gene. We assessed the pathogenicity of these two variants using cultured-cells and zebrafish model. An in vitro kinase assay of human CDK8 showed that enzymes with a p.G28A or p.N156S substitution showed decreased kinase activity. An in vivo assays of zebrafish overexpression analyses also showed that the p.G28A and p.N156S alleles were hypomorphic alleles. Importantly, the inhibition of CDK8 kinase activity in zebrafish embryos using a specific chemical inhibitor induced craniofacial and heart defects similar to the patients' phenotype. Taken together, zebrafish studies showed that non-synonymous variants in the kinase domain of CDK8 act as hypomorphic alleles causing human congenital disorder.
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