Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 106, Issue 5, Pages 717-725Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2020.04.001
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Funding
- NIH Common Fund, through the Office of Strategic Coordination and Office of the NIH [U01HG007709, U01HG007942]
- NIH from NINDS [R24OD022005, U54]
- Hunan Provincial Major Science and Technology Project [2019SK1010]
- National Natural Science Foundation of China [81801136, 81974206]
- NIH [U01HG007709, U54HD083092]
- CIHR [MFE-164712]
- American Academy of Neurology, Child Neurology Foundation
- Burroughs Wellcome Fund
- McNair Medical Institute at the Robert
- Janice McNair Foundation
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We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. In contrast, the CDK19 p.Tyr32His and p.Thr196Ala variants identified in the affected individuals fail to rescue the loss of Cdk8 and behave as null alleles. Additionally, neuronal RNAi-mediated knockdown of Cdk8 in flies results in semi-lethality. The few eclosing flies exhibit severe seizures and a reduced lifespan. Both phenotypes are fully suppressed by moderate expression of the CDK19 reference cDNA but not by expression of the two variants. Finally, loss of Cdk8 causes an obvious loss of boutons and synapses at larval neuromuscular junctions (NMJs). Together, our findings demonstrate that human CDK19 fully replaces the function of Cdk8 in the fly, the human disease-associated CDK19 variants behave as strong loss-of-function variants, and deleterious CDK19 variants underlie a syndromic neurodevelopmental disorder.
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