NIMA-related kinase family at the nexus of skeletal development and congenital arthrogryposis: coordinated regulation of cell cycle and ciliary dynamics

BackgroundThe NIMA-related kinase (NEK) family comprises a group of serine/threonine kinases that play pivotal roles in cell cycle control. Emerging evidence has demonstrated that loss-of-function (LOF) mutations in NEK family members, particularly NEK1 and NEK9, cause skeletal and joint developmental abnormalities.ResultsThis review synthesizes clinical, genetic, and functional evidence from patient-based studies, cell models, and animal experiments to elucidate the pathogenic mechanisms. Loss-of-function of these two kinases can disrupt cell cycle progression through distinct mechanisms, such as arrest at different phases (e.g., S phase and G2/M phase). Although the arrest stages differ, both can be accompanied by defects in primary cilia formation, which in turn disrupt cilia-dependent Hedgehog and Wnt signaling. The interplay between cell cycle dysregulation and ciliary dysfunction is tightly intertwined in these diseases; however, it remains difficult to clearly distinguish cause from effect between the two. NEK kinases may drive pathology through multiple pathways, including directly affecting cilia assembly and interfering with cell cycle progression. This dual impairment of the cell cycle and cilia leads to chondrocyte proliferation failure, growth plate disorganization, and joint contractures. Genotype–phenotype correlations reveal that missense versus truncating NEK1 mutations cause divergent skeletal phenotypes, while NEK9 mutations underlie lethal congenital contracture syndrome. Emerging evidence also suggests potential modifying roles for NEK7 in inflammation and endosomal trafficking.ConclusionIn conclusion, NEK-associated skeletal disorders arise from a combination of cell cycle defects and ciliary abnormalities, rather than being caused by either factor alone. Consequently, therapeutic strategies targeting cell cycle regulation or related downstream pathways may offer new avenues for treating these severe pediatric skeletal diseases.