Novel KIF22 variants disrupt mitosis in human chondrocytes and expand SEMDJL2 mechanisms
Year: 2026
Type: article
Abstract: Spondyloepimetaphyseal dysplasia with joint laxity, type 2 (SEMDJL2) is a rare skeletal disorder caused by pathogenic variants in KIF22, a mitotic chromokinesin that generates polar ejection forces (PEFs) to ensure proper chromosome alignment and segregation. Although SEMDJL2-associated variants disrupt chromosome segregation in epithelial cells, their effects in chondrocytes remain poorly understood. Here, we examined the functional consequences of the hotspot, dominant variant R149Q, a recently reported recessive variant R49Q, and two new dominant variants, P144T and E222Q, in human chondrocytes. Both novel variants were found in individuals with classic SEMDJL2 phenotypes. P144T and E222Q retained PEF-generating activity, whereas R49Q displayed reduced PEFs, consistent with their inheritance patterns. Live-cell imaging revealed that all variants perturbed mitosis. The heterozygous variants (P144T, E222Q, and R149Q) dominantly impeded anaphase chromosome segregation and spindle pole separation, supporting classification as likely pathogenic. In contrast, R49Q produced milder, partially penetrant defects, consistent with reduced and dysregulated motor activity. These findings support a model that defines two mechanistic classes of KIF22 dysregulation: constitutive activation in heterozygous variants, which fail to inactivate KIF22 at anaphase onset, and mixed-state dysregulation in the recessive R49Q variant. This work broadens the mechanistic framework linking KIF22 variants to disrupted chondrocyte mitosis and SEMDJL2.
Source: Molecular Biology of the Cell
Authors: Amila Šemić, Kazette Yuen Yu Chan, Pricila Bernardi, Karina C. Silveira, Cynthia Silveira, Denise P. Cavalcanti, Peter Kannu, Jason Stumpff
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7165036743