PUBLICATION
CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants
- Authors
- 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.G., 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., Kosaki, K.
- ID
- ZDB-PUB-210128-5
- Date
- 2021
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 23(6): 1050-1057 (Journal)
- Registered Authors
- Abe, Kota, Ishitani, Shizuka
- Keywords
- none
- MeSH Terms
-
- Animals
- Cyclin-Dependent Kinases/genetics
- Gain of Function Mutation
- Humans
- Infant
- Intellectual Disability*
- Mutation, Missense
- Neurodevelopmental Disorders*
- Zebrafish/genetics
- PubMed
- 33495529 Full text @ Genet. Med.
Citation
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.G., 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., Kosaki, K. (2021) CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants. Genetics in medicine : official journal of the American College of Medical Genetics. 23(6):1050-1057.
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 CDK19G28R and CDK19Y32H.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping