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

Animals Cyclin-Dependent Kinases / genetics Gain of Function Mutation Humans Infant Intellectual Disability Mutation, Missense Neurodevelopmental Disorders Zebrafish / genetics

Journal

Genetics in medicine : official journal of the American College of Medical Genetics

ISSN: 1530-0366

Titre abrégé: Genet Med

Pays: United States

ID NLM: 9815831

Informations de publication

Date de publication:
06 2021

Historique:

received: 19 08 2020

accepted: 22 12 2020

revised: 18 12 2020

pubmed: 27 1 2021

medline: 8 7 2021

entrez: 26 1 2021

Statut: ppublish

Résumé

To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. 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 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%). 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.

Identifiants

DOI: 10.1038/s41436-020-01091-9 PMID: 33495529

pubmed: 33495529

doi: 10.1038/s41436-020-01091-9

pii: S1098-3600(21)05205-9

doi:

Substances chimiques

CDK19 protein, human EC 2.7.11.22

Cyclin-Dependent Kinases EC 2.7.11.22

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1050-1057

Subventions

Organisme : NCATS NIH HHS

ID : UL1 TR002538

Pays : United States

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