Research ExplorerPublicationsCDK19-related disorder results from both loss-of-function an...

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

Standard

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants. / Zarate, Yuri A; Uehara, Tomoko; Abe, Kota; Oginuma, Masayuki; Harako, Sora; Ishitani, Shizuka; Lehesjoki, Anna-Elina; Bierhals, Tatjana; Kloth, Katja; Ehmke, Nadja; Horn, Denise; Holtgrewe, Manuel; Anderson, Katherine; Viskochil, David; Edgar-Zarate, Courtney L; Sacoto, Maria J Guillen; Schnur, Rhonda E; Morrow, Michelle M; Sanchez-Valle, Amarilis; Pappas, John; Rabin, Rachel; Muona, Mikko; Anttonen, Anna-Kaisa; Platzer, Konrad; Luppe, Johannes; Gburek-Augustat, Janina; Kaname, Tadashi; Okamoto, Nobuhiko; Mizuno, Seiji; Kaido, Yusaku; Ohkuma, Yoshiaki; Hirose, Yutaka; Ishitani, Tohru; Kosaki, Kenjiro.

In: GENET MED, Vol. 23, No. 6, 06.2021, p. 1050-1057.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Zarate, YA, 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, CL, Sacoto, MJG, Schnur, RE, Morrow, MM, 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', GENET MED, vol. 23, no. 6, pp. 1050-1057. https://doi.org/10.1038/s41436-020-01091-9

APA

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., ... Kosaki, K. (2021). CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants. GENET MED, 23(6), 1050-1057. https://doi.org/10.1038/s41436-020-01091-9

Vancouver

Zarate YA, Uehara T, Abe K, Oginuma M, Harako S, Ishitani S et al. CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants. GENET MED. 2021 Jun;23(6):1050-1057. https://doi.org/10.1038/s41436-020-01091-9

Bibtex

@article{3830cd49f1204a7b87321f27a5ae251d,
title = "CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants",
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.",
author = "Zarate, {Yuri A} and Tomoko Uehara and Kota Abe and Masayuki Oginuma and Sora Harako and Shizuka Ishitani and Anna-Elina Lehesjoki and Tatjana Bierhals and Katja Kloth and Nadja Ehmke and Denise Horn and Manuel Holtgrewe and Katherine Anderson and David Viskochil and Edgar-Zarate, {Courtney L} and Sacoto, {Maria J Guillen} and Schnur, {Rhonda E} and Morrow, {Michelle M} and Amarilis Sanchez-Valle and John Pappas and Rachel Rabin and Mikko Muona and Anna-Kaisa Anttonen and Konrad Platzer and Johannes Luppe and Janina Gburek-Augustat and Tadashi Kaname and Nobuhiko Okamoto and Seiji Mizuno and Yusaku Kaido and Yoshiaki Ohkuma and Yutaka Hirose and Tohru Ishitani and Kenjiro Kosaki",
year = "2021",
month = jun,
doi = "10.1038/s41436-020-01091-9",
language = "English",
volume = "23",
pages = "1050--1057",
journal = "GENET MED",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

RIS

TY - JOUR

T1 - CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

AU - Zarate, Yuri A

AU - Uehara, Tomoko

AU - Abe, Kota

AU - Oginuma, Masayuki

AU - Harako, Sora

AU - Ishitani, Shizuka

AU - Lehesjoki, Anna-Elina

AU - Bierhals, Tatjana

AU - Kloth, Katja

AU - Ehmke, Nadja

AU - Horn, Denise

AU - Holtgrewe, Manuel

AU - Anderson, Katherine

AU - Viskochil, David

AU - Edgar-Zarate, Courtney L

AU - Sacoto, Maria J Guillen

AU - Schnur, Rhonda E

AU - Morrow, Michelle M

AU - Sanchez-Valle, Amarilis

AU - Pappas, John

AU - Rabin, Rachel

AU - Muona, Mikko

AU - Anttonen, Anna-Kaisa

AU - Platzer, Konrad

AU - Luppe, Johannes

AU - Gburek-Augustat, Janina

AU - Kaname, Tadashi

AU - Okamoto, Nobuhiko

AU - Mizuno, Seiji

AU - Kaido, Yusaku

AU - Ohkuma, Yoshiaki

AU - Hirose, Yutaka

AU - Ishitani, Tohru

AU - Kosaki, Kenjiro

PY - 2021/6

Y1 - 2021/6

N2 - 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.

AB - 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.

U2 - 10.1038/s41436-020-01091-9

DO - 10.1038/s41436-020-01091-9

M3 - SCORING: Journal article

C2 - 33495529

VL - 23

SP - 1050

EP - 1057

JO - GENET MED

JF - GENET MED

SN - 1098-3600

IS - 6

ER -