Loss-of-function mutations inKIF14cause severe microcephaly and kidney development defects in humans and zebrafish

Abstract

Mutations in KIF14 have previously 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 cytokinesis and has not previously been shown to be involved in cilia-related functions. Here, we analysed four families with fetuses presenting with the syndromic form and harbouring biallelic variants in KIF14. Our functional analyses showed that the identified variants severely impact the activity of KIF14 and likely correspond to loss-of-function mutations. Analysis in human fetal 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 kif14 mutant zebrafish line showed a conserved role for this mitotic kinesin. Interestingly, ciliopathy-associated phenotypes were also present in mutant embryos, supporting a potential direct or indirect role for KIF14 at cilia. However, our in vitro and in vivo analyses did not provide evidence of a direct role for KIF14 in ciliogenesis and suggested that loss of kif14 causes ciliopathy-like phenotypes through an accumulation of mitotic cells in ciliated tissues. Altogether, our results demonstrate that KIF14 mutations result in a severe syndrome associating microcephaly and RHD through its conserved function in cytokinesis during kidney and brain development.

Cytokinetic bridge triggers de novo lumen formation in vivo

“…2d, e). These findings are consistent with an analysis of human fetal tissues where the accumulation of KIF14-positive midbodies were identified in the lumen of ureteric bud tips 29 .…”

Structural basis of mechano-chemical coupling by the mitotic kinesin KIF14

“…The KIF14 molecule is also similar to other microtubule plus end directed motile kinesins in having two motor domain joined by a coiled coil dimerization domain located C-terminal to the motor domain and a ~15 residues long peptide, the neck-linker, connecting the motor and coiled coil domains (Verhey et al, 2015). KIF14 also contains an N-terminal extension with a PRC1 (protein-regulating cytokinesis 1) binding domain (Arora et al, 2014;Gruneberg et al, 2006;Reilly et al, 2018).…”

“…Its overexpression is associated with tumor progression and resistance to anti-cancer drugs in several cancers for which is considered an oncogene (Corson and Gallie, 2006;Corson et al, 2005;Lucanus and Yip, 2017;Schiewek et al, 2018;Thériault et al, 2012;Wang et al, 2016). Mutations in KIF14 are also associated with neural and kidney development defects (Moawia et al, 2017;Reilly et al, 2018).…”

Ciliary kinesins beyond IFT: Cilium length, disassembly, cargo transport and signalling

“…In addition, as the presence of cystic kidneys and developmental brain defects in the affected foetuses were reminiscent of Meckel‐Grüber syndrome, KIF14 was therefore termed MKS12 . These observations suggested a potential link between KIF14 and PC, however, our recent works failed to establish such a functional link [Reilly et al ., ].…”