ABSTRACT
The chromokinesin KIF22 generates pushing forces that contribute to mitotic chromosome congression and alignment. Mutations in 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 assessed whether pathogenic mutations affect the function of KIF22 in mitosis and demonstrate that mutations do not result in a loss of KIF22 function. Instead, mutations disrupted 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 phenocopied the effects of pathogenic mutations. These findings offer insight into the mechanism by which mutations in KIF22 may affect human development, the consequences of imbalance between polar ejection forces and antiparallel microtubule sliding in anaphase, and potential mechanisms of KIF22 regulation.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
We have revised the manuscript in response to suggestions and questions received via ASAPbio Crowd Review. Changes include new analyses presented in Fig 3 E-F, as well as changes to the text to improve clarity.