Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

Abstract

The chromokinesin KIF22 uses plus end-directed motility and direct binding to chromosome arms to generate 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 coiled-coil domain of the KIF22 tail. The mechanism by which these mutations affect development is unknown. 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. Pathogenic mutations did not alter the localization or prometaphase function of KIF22. 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, a phosphomimetic mutation, which constitutively activates 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 balance between polar ejection forces and antiparallel microtubule sliding in anaphase, and potential mechanisms of KIF22 regulation.

ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

“…Expression of a constitutively active KIF22 displays similar properties, suggesting that these mutations attenuate the autoinhibition of KIF22 (Thompson et al, 2021). There is also suggestive evidence that mutations in KIF7 that relieve autoinhibition may contribute to human disease (Blasius et al, 2021;Thompson et al, 2021). Taken together, mutations that attenuate or abolish the autoinhibition…”

“…Pathogenic mutations in KIF22, observed in two adjacent amino acids in the motor domain or a single amino acid within the coiled-coil domain, disrupt chromosome segregation in anaphase. Expression of a constitutively active KIF22 displays similar properties, suggesting that these mutations attenuate the autoinhibition of KIF22 (Thompson et al, 2021). There is also suggestive evidence that mutations in KIF7 that relieve autoinhibition may contribute to human disease (Blasius et al, 2021;Thompson et al, 2021).…”

“…The kinesin KIF22 contributes to the alignment of the chromosome during mitosis. Heterozygous mutations in KIF22 result in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (Boyden et al, 2011;Min et al, 2011;Thompson et al, 2021). Pathogenic mutations in KIF22, observed in two adjacent amino acids in the motor domain or a single amino acid within the coiled-coil domain, disrupt chromosome segregation in anaphase.…”