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

Thomas Robert¹, Anne-Catherine Dock-Bregeon¹, Pierre Colas¹

¹Laboratory of Integrative Biology of Marine Models, Station Biologique de Roscoff, Sorbonne Université/CNRS, Roscoff, France.

Molecular Genetics & Genomic Medicine

|August 9, 2021

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.

Insights

Truncated CDK10 and CycM variants retain heterodimerization but lose kinase activity, leading to Al Kaissi and STAR syndromes due to proteasomal degradation and reduced CDK10/CycM function.

Area of Science:

Molecular Biology
Genetics
Biochemistry

Background:

Cyclin M (CycM)-dependent kinase CDK10 is poorly understood.
Loss-of-function mutations in CDK10 or CycM cause Al Kaissi and STAR syndromes, respectively.
Two specific mutations may allow truncated CDK10 and CycM variants to be expressed.

Purpose of the Study:

To functionally characterize two truncated CDK10/CycM variants.
To assess their heterodimerization, kinase activity, and stability.
To understand their role in Al Kaissi and STAR syndromes.

Main Methods:

Structural modeling to predict heterodimer formation.
In vitro kinase assays.
Yeast two-hybrid interaction studies.
Expression and stability analysis in human cells.

Main Results:

Both truncated variants successfully formed CDK10/CycM heterodimers.
The CycM variant partially activated CDK10 in vitro; the CDK10 variant remained inactive.
Truncated variants showed significant proteasomal degradation in human cells.

Conclusions:

Al Kaissi syndrome is linked to a complete loss of CDK10/CycM activity.
STAR syndrome is associated with a partial loss of CDK10/CycM activity.
Proteasomal degradation contributes to the loss of function in these syndromes.

Read full analysis

Keywords:

Al Kaissi syndrome CDK10 STAR syndrome cyclin M interaction profiling protein kinase

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