Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

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Abstract

The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the a2 helix of the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the KIF22 tail. We demonstrate that pathogenic mutations do not result in a loss of KIF22's functions in early mitosis. Instead, mutations disrupt chromosome segregation in anaphase, resulting in reduced proliferation, abnormal daughter cell nuclear morphology, and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase. Consistent with this model, constitutive activation of the motor via a known site of phosphoregulation in the tail phenocopied the effects of pathogenic mutations. These results suggest the motor domain a2 helix may be an important site for regulation of KIF22 activity at the metaphase to anaphase transition. In support of this conclusion, mimicking phosphorylation of a2 helix residue T158 also prevents inactivation of KIF22 in anaphase. These findings demonstrate the importance of both the head and tail of the motor in regulating the activity of KIF22 and offer insight into the cellular consequences of preventing KIF22 inactivation and disrupting force balance in anaphase.

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All data generated or analyzed during this study are included in the manuscript and supporting files. Source Data files have been provided for Figure 2, Figure 2- Figure Supplement 1, Figure 3, Figure 4, Figure 4- Figure Supplement 1, Figure 5, Figure 6, Figure 6- Figure Supplement 1, Figure 7, Figure 8, Figure 8- Figure Supplement 1, Figure 9, Figure 9- Figure Supplement 1, Figure 9- Figure Supplement 2, and Figure 9- Figure Supplement 3.

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Alex F Thompson

Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Patrick R Blackburn

Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0658-1275
Noah S Arons

Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Sarah N Stevens

Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Dusica Babovic-Vuksanovic

Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States

Competing interests
The authors declare that no competing interests exist.
Jane B Lian

Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Eric W Klee

Biomedical Informatics, Mayo Clinic, Rochester, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2946-5795
Jason Stumpff

Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States

For correspondence
jstumpff@uvm.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0392-1254

Funding

National Institutes of Health (F31AR074887)

Alex F Thompson

National Institutes of Health (R01GM130556)

Jason Stumpff

National Institutes of Health (R01GM121491)

Jason Stumpff

National Institutes of Health (R35GM144133)

Jason Stumpff

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.