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.
Highlights
Cyclin-dependent kinase 8 (CDK8) is an evolutionarily conserved serine/threonine kinase that belongs to the CDK/Cyclin module of the mediator complex
A recent study reported the cases of 12 patients with eight heterozygous non-synonymous variants in the kinase domain (21–335 amino acids, Fig. 1a)[5] of the CDK8 gene who presented with characteristic facial features, congenital heart disorders and intellectual disability[6]
We report an in vivo functional analysis in a zebrafish model with de novo amino-acid substitutions (p.G28A and N156S) in the kinase domain of CDK8, as detected in 2 patients with syndromic intellectual disability
Summary
Cyclin-dependent kinase 8 (CDK8) is an evolutionarily conserved serine/threonine kinase that belongs to the CDK/Cyclin module of the mediator complex. A recent study reported the cases of 12 patients with eight heterozygous non-synonymous variants in the kinase domain (21–335 amino acids, Fig. 1a)[5] of the CDK8 gene who presented with characteristic facial features, congenital heart disorders and intellectual disability[6]. An in vitro functional analysis of the eight types of variants in the kinase domain of CDK8 demonstrated that CDK8-associated disorder is caused by hypomorphic alleles of CDK86. The mechanistic basis of CDK8-associated disorder in vivo has yet to be determined. We report an in vivo functional analysis in a zebrafish model with de novo amino-acid substitutions (p.G28A and N156S) in the kinase domain of CDK8, as detected in 2 patients with syndromic intellectual disability
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