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

Abstract : Background: DK10 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.
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Submitted on : Monday, September 13, 2021 - 3:26:50 PM
Last modification on : Wednesday, September 15, 2021 - 3:31:08 AM

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Thomas Robert, Anne‐catherine Dock‐bregeon, Pierre Colas. Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders. Molecular Genetics & Genomic Medicine, Wiley Periodicals, Inc. inPress, ⟨10.1002/mgg3.1782⟩. ⟨hal-03342727⟩

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