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CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants
- Source :
- Genetics in Medicine. 23:1050-1057
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
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.
- 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
Subjects
Details
- ISSN :
- 10983600
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- Genetics in Medicine
- Accession number :
- edsair.doi.dedup.....5813c2192055f297fcafe358e6d9a2ec