KIF22 dysfunction: linking mitotic mechanics to skeletal disease

Dominant and recessive variants in KIF22 cause the same skeletal disorder, spondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2), characterised by disproportionate short stature, platyspondyly, generalised joint laxity and slender tubular bones. How variants with different effects on a broadly expressed mitotic motor converge on a predominantly skeletal disorder is unresolved. Here, we review the genetic, functional and experimental evidence bearing on this question. Genetic evidence argues against haploinsufficiency as the mechanism of dominant disease, and functional studies show that dominant and recessive variants, despite differing effects on polar ejection force generation, share defective inactivation of KIF22 at anaphase. We therefore propose that SEMDJL2 is a disorder of mistimed motor activity rather than KIF22 deficiency. In chondrocyte models, these variants cause chromosome-segregation errors and impaired proliferation, providing a plausible route to reduced longitudinal bone growth. Why chondrocytes are particularly affected remains unclear; we consider whether they incur more mitotic errors than other proliferating cells or tolerate them less well. Since reduced proliferation does not readily explain joint laxity and dislocations, we also evaluate evidence that extracellular matrix homeostasis is altered, including reduced sulfated proteoglycans in patient fibroblasts and reduced SOX9 transcriptional activity in chondrocyte models. Finally, we outline experiments that would distinguish these mechanisms and determine whether matrix abnormalities are a consequence of mitotic dysfunction or an independent contributor.