Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

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.

The spindle protein CKAP2 regulates microtubule dynamics and ensures faithful chromosome segregation

“…Similar anaphase movement defects have been reported to occur in HeLa-Kyoto cells expressing mutants of Kif22, a mitotic kinesin motor (40). These abnormal anaphase movements are thought to result from failure of Kif22 inactivation at anaphase onset, thereby disrupting force balance at anaphase (40). Donut-shaped nuclei have also been observed in cells 14 overexpressing TPX2, and these cells were found to house a single centrosome inside their hollow surface (12), similar to our observations in CKAP2-KO cells (Supplementary Figure 3).…”

“…Moreover, some CKAP2-KO clones display reduced speed of chromosome separation (Supplementary Figure 7). Similar anaphase movement defects have been reported to occur in HeLa-Kyoto cells expressing mutants of Kif22, a mitotic kinesin motor (40). These abnormal anaphase movements are thought to result from failure of Kif22 inactivation at anaphase onset, thereby disrupting force balance at anaphase (40).…”

Chromosome size-dependent polar ejection force impairs mammalian mitotic error correction

“…Overexpression of the Drosophila orthologue of Kif22/Kid induces attachment errors, which elude error correction (Cane et al, 2013b), suggesting that polar ejection forces can contribute to attachment stabilization, possibly by increasing kinetochore tension. In mammalian cells, tension perturbations are needed to understand how the error correction machinery responds to tension changes and how the magnitude of polar ejection force—which in principle can vary throughout mitosis (Ke et al, 2009; Thompson et al, 2022) and across different chromosomes—impacts kinetochore tension and attachment stability.…”

Spondyloepimetaphyseal dysplasia with joint laxity type 2: Aggregating the literature and reporting on the life of a 66‐year‐old man

“…Heterozygous pathogenic variants in the Kinesin Family Member 22 gene (KIF22, 16p11; MIM:603213) confers SEMDJL2 through autosomal dominant inheritance (Boyden et al, 2011; Min et al, 2011). KIF22 mRNA is expressed in bone, cartilage, joint capsule, ligament, and skin (Fagerberg et al, 2014), and recent results suggest that KIF22 is essential for the transition between metaphase and anaphase (Thompson et al, 2022). Pathogenic variants of KIF22 result in chromosomal recongression during anaphase, leading to incomplete cellular division (Thompson et al, 2022).…”

“…KIF22 mRNA is expressed in bone, cartilage, joint capsule, ligament, and skin (Fagerberg et al, 2014), and recent results suggest that KIF22 is essential for the transition between metaphase and anaphase (Thompson et al, 2022). Pathogenic variants of KIF22 result in chromosomal recongression during anaphase, leading to incomplete cellular division (Thompson et al, 2022). SEMDJL2-pathogenic variants in KIF22 typically result from changes in two codons in a genetic hotspot (c.442C > T, p.Pro148Ser; c.443C > T, p.Pro148Leu; c.446G > A, p.Arg149Gln; c.446G > T, p.-Arg149Leu) (Boyden et al, 2011).…”