1. CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants
- Author
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Denise Horn, Anna-Elina Lehesjoki, Janina Gburek-Augustat, Amarilis Sanchez-Valle, Kenjiro Kosaki, Katherine Anderson, Anna-Kaisa Anttonen, Tohru Ishitani, Katja Kloth, Manuel Holtgrewe, Sora Harako, Rhonda E. Schnur, Maria J. Guillen Sacoto, Yutaka Hirose, Seiji Mizuno, Shizuka Ishitani, Kota Abe, Tadashi Kaname, Yusaku Kaido, Johannes Luppe, Nadja Ehmke, Michelle M. Morrow, John Pappas, Tatjana Bierhals, Masayuki Oginuma, David Viskochil, Yoshiaki Ohkuma, Tomoko Uehara, Konrad Platzer, Courtney L. Edgar-Zarate, Rachel Rabin, Yuri A. Zarate, Mikko Muona, Nobuhiko Okamoto, Department of Medical and Clinical Genetics, University of Helsinki, Medicum, HUSLAB, Anna-Elina Lehesjoki / Principal Investigator, Neuroscience Center, and Helsinki University Hospital Area
- Subjects
0301 basic medicine ,GENES ,CDK8 ,Mutation, Missense ,PROTEIN ,030105 genetics & heredity ,SEQUENCE ,03 medical and health sciences ,Neurodevelopmental disorder ,Intellectual Disability ,medicine ,Animals ,Humans ,Missense mutation ,Kinase activity ,Zebrafish ,Genetics (clinical) ,Loss function ,MEDIATOR COMPLEX ,Genetics ,biology ,Autophosphorylation ,Infant ,biology.organism_classification ,medicine.disease ,Cyclin-Dependent Kinases ,Hypotonia ,MED12 ,030104 developmental biology ,Protein kinase domain ,Neurodevelopmental Disorders ,Gain of Function Mutation ,3111 Biomedicine ,medicine.symptom - Abstract
Purpose To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. Methods Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19(G28R) and CDK19(Y32H). Results We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%). Conclusion CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.
- Published
- 2021
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