Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders

Abstract Background CDK10 is a poorly known cyclin M (CycM)‐dependent kinase. Loss‐of‐function mutations in the genes encoding CycM or CDK10 cause, respectively, STAR or Al Kaissi syndromes, which present a constellation of malformations and dysfunctions. Most reported mutations abolish gene express...

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Autores principales:	Thomas Robert, Anne‐Catherine Dock‐Bregeon, Pierre Colas
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Al Kaissi syndrome CDK10 cyclin M interaction profiling protein kinase STAR syndrome Genetics QH426-470
Acceso en línea:	https://doaj.org/article/a9b71a335ec247d798d8c68cdf527e63
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spelling	oai:doaj.org-article:a9b71a335ec247d798d8c68cdf527e632021-11-10T16:39:23ZFunctional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders2324-926910.1002/mgg3.1782https://doaj.org/article/a9b71a335ec247d798d8c68cdf527e632021-10-01T00:00:00Zhttps://doi.org/10.1002/mgg3.1782https://doaj.org/toc/2324-9269Abstract Background CDK10 is a poorly known cyclin M (CycM)‐dependent kinase. Loss‐of‐function mutations in the genes encoding CycM or CDK10 cause, respectively, STAR or Al Kaissi syndromes, which present a constellation of malformations and dysfunctions. Most reported mutations abolish gene expression, but two mutations found in 3’ exons could allow the expression of CDK10 and CycM truncated variants. Methods We built a structural model that predicted a preserved ability of both variants to form a CDK10/CycM heterodimer. Hence, we functionally characterized these two truncated variants by determining their capacity to heterodimerize and form an active protein kinase when expressed in insect cells, by examining their two‐hybrid interaction profiles when expressed in yeast, and by observing their expression level and stability when expressed in human cells. Results Both truncated variants retain their ability to form a CDK10/CycM heterodimer. While the CycM variant partially activates CDK10 activity in vitro, the CDK10 variant remains surprisingly inactive. Expression in human cells revealed that the CDK10 and CycM variants are strongly and partially degraded by the proteasome, respectively. Conclusion Our results point to a total loss of CDK10/CycM activity in the Al Kaissi patient and a partial loss in the STAR patients.Thomas RobertAnne‐Catherine Dock‐BregeonPierre ColasWileyarticleAl Kaissi syndromeCDK10cyclin Minteraction profilingprotein kinaseSTAR syndromeGeneticsQH426-470ENMolecular Genetics & Genomic Medicine, Vol 9, Iss 10, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Al Kaissi syndrome CDK10 cyclin M interaction profiling protein kinase STAR syndrome Genetics QH426-470
spellingShingle	Al Kaissi syndrome CDK10 cyclin M interaction profiling protein kinase STAR syndrome Genetics QH426-470 Thomas Robert Anne‐Catherine Dock‐Bregeon Pierre Colas Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders
description	Abstract Background CDK10 is a poorly known cyclin M (CycM)‐dependent kinase. Loss‐of‐function mutations in the genes encoding CycM or CDK10 cause, respectively, STAR or Al Kaissi syndromes, which present a constellation of malformations and dysfunctions. Most reported mutations abolish gene expression, but two mutations found in 3’ exons could allow the expression of CDK10 and CycM truncated variants. Methods We built a structural model that predicted a preserved ability of both variants to form a CDK10/CycM heterodimer. Hence, we functionally characterized these two truncated variants by determining their capacity to heterodimerize and form an active protein kinase when expressed in insect cells, by examining their two‐hybrid interaction profiles when expressed in yeast, and by observing their expression level and stability when expressed in human cells. Results Both truncated variants retain their ability to form a CDK10/CycM heterodimer. While the CycM variant partially activates CDK10 activity in vitro, the CDK10 variant remains surprisingly inactive. Expression in human cells revealed that the CDK10 and CycM variants are strongly and partially degraded by the proteasome, respectively. Conclusion Our results point to a total loss of CDK10/CycM activity in the Al Kaissi patient and a partial loss in the STAR patients.
format	article
author	Thomas Robert Anne‐Catherine Dock‐Bregeon Pierre Colas
author_facet	Thomas Robert Anne‐Catherine Dock‐Bregeon Pierre Colas
author_sort	Thomas Robert
title	Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders
title_short	Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders
title_full	Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders
title_fullStr	Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders
title_full_unstemmed	Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders
title_sort	functional characterization of cdk10 and cyclin m truncated variants causing severe developmental disorders
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/a9b71a335ec247d798d8c68cdf527e63
work_keys_str_mv	AT thomasrobert functionalcharacterizationofcdk10andcyclinmtruncatedvariantscausingseveredevelopmentaldisorders AT annecatherinedockbregeon functionalcharacterizationofcdk10andcyclinmtruncatedvariantscausingseveredevelopmentaldisorders AT pierrecolas functionalcharacterizationofcdk10andcyclinmtruncatedvariantscausingseveredevelopmentaldisorders
_version_	1718439902618583040

Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders

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