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

Yuri A. Zarate, Tomoko Uehara, Kota Abe, Masayuki Oginuma, Sora Harako, Shizuka Ishitani, Anna Elina Lehesjoki, Tatjana Bierhals, Katja Kloth, Nadja Ehmke, Denise Horn, Manuel Holtgrewe, Katherine Anderson, David Viskochil, Courtney L. Edgar-Zarate, Maria J.Guillen Sacoto, Rhonda E. Schnur, Michelle M. Morrow, Amarilis Sanchez-Valle, John PappasRachel Rabin, Mikko Muona, Anna Kaisa Anttonen, Konrad Platzer, Johannes Luppe, Janina Gburek-Augustat, Tadashi Kaname, Nobuhiko Okamoto, Seiji Mizuno, Yusaku Kaido, Yoshiaki Ohkuma, Yutaka Hirose, Tohru Ishitani, Kenjiro Kosaki

研究成果: Article査読


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.

ジャーナルGenetics in Medicine
出版ステータスPublished - 2021 6

ASJC Scopus subject areas

  • 遺伝学(臨床)


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