CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Tools

Item Type:	Article
Title:	CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants
Creators Name:	Zarate, Y.A., Uehara, T., Abe, K., Oginuma, M., Harako, S., Ishitani, S., Lehesjoki, A.E., Bierhals, T., Kloth, K., Ehmke, N., Horn, D., Holtgrewe, M., Anderson, K., Viskochil, D., Edgar-Zarate, C.L., Sacoto, M.J.Guillen, Schnur, R.E., Morrow, M.M., Sanchez-Valle, A., Pappas, J., Rabin, R., Muona, M., Anttonen, A.K., Platzer, K., Luppe, J., Gburek-Augustat, J., Kaname, T., Okamoto, N., Mizuno, S., Kaido, Y., Ohkuma, Y., Hirose, Y., Ishitani, T. and Kosaki, K.
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.
Keywords:	Cyclin-Dependent Kinases, Gain of Function Mutation, Intellectual Disability, Missense Mutation, Neurodevelopmental Disorders, Animals, Zebrafish
Source:	Genetics in Medicine
ISSN:	1098-3600
Publisher:	Nature Publishing Group
Volume:	23
Number:	6
Page Range:	1050-1057
Number of Pages:	8
Date:	June 2021
Official Publication:	https://doi.org/10.1038/s41436-020-01091-9
PubMed:	View item in PubMed

Repository Staff Only: item control page