Abstract
KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients’ neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.
Highlights
KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics
We identified a de novo variant (NM_ 001252100.1, c.2032A>C, p.Ile678Leu) in the KIF21B gene in a first patient (P1) presenting with developmental delay, learning and motor disabilities, associated with isolated complete agenesis of the corpus callosum (ACC) (Fig. 1a, e, Table 1, Supplementary Note 1)
The three identified KIF21B missense variants occur within highly conserved residues positioned in the motor domain (NM_001252100.1, c.937C>A, p.Gln313LysP2), the regulatory coiled-coil region (NM_001252100.1, c.3001G>A, p.Ala1001Thr-patient 3 (P3)), and the coiled-coil domain (NM_001252100.1, c.2032A>C, p.Ile678Leu-P1) (Fig. 1h, Supplementary Fig. 1a–c)
Summary
KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. Kinesin superfamily proteins (KIFs) are important molecular motors that control MT organization and dynamics in both axons and dendrites and mediate intracellular transport of various cargo, including vesicles, organelles, cellular proteins and mRNAs, along MTs1,2 The importance of both the force-generating and MT-regulating functions of KIFs for brain development has become evident with loss of function studies demonstrating defects in mitosis[3,4,5,6,7,8,9], cytokinesis[10,11], polarity[3], migration[12,13,14], axonal growth and branching[14,15,16,17,18], survival[19] and synaptogenesis[20,21,22,23,24]. KIF21B functions can be modulated by neuronal activity, which favors KIF21B trafficking activity at the expense of MT dynamics regulatory function[44] as well as through an autoinhibitory interaction between the N-terminal motor domain and an internal regulatory coiled-coil region (rCC)[42,46]
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