Loss of function mutations in KIF14 cause severe microcephaly and kidney development defects in humans and zebrafish

Mutations in KIF14havepreviously been associated with either severe, isolated or syndromic microcephaly with renal hypodysplasia (RHD). Syndromic microcephaly-RHD was strongly reminiscent of clinical ciliopathies, relating to defects of the primary cilium, a signalling organelle present on the surface of many quiescent cells.KIF14 encodes a mitotic kinesin which plays a key role at the midbody during cytokinesisand has not previously been shown to be involved in cilia-related functions. Here, we analysed four families with foetuses presenting with the syndromic form and harbouring biallelic variantsin KIF14. Our functional analyses showthat the identified variantsseverely impact the activity of KIF14 and likely correspond to loss-of-function mutations. Analysis in human foetal tissues further revealed the accumulation of KIF14-positive midbody remnants in the lumen of ureteric bud tips indicating a shared function of KIF14 during brain and kidney development. Subsequently, analysis of a kif14mutant zebrafish line showed a conserved role for this mitotic kinesin. Interestingly, ciliopathy-associated phenotypes were also present in mutant embryos,supportinga potential direct or indirect role for KIF14 at cilia. However, our in vitro and in vivoanalyses did not provide evidence of a direct role for KIF14 in ciliogenesis and suggestedthat loss ofkif14causesciliopathy-like phenotypesthrough an accumulation ofmitotic cells in ciliated tissues. Altogether, our results demonstrate that KIF14 mutations result in a severe syndrome associating microcephaly and RHD through its conserved functionin cytokinesis during kidney and brain development.