Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity

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.

Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

“…KIF21B is expressed in brain, eyes, and spleen ( Marszalek et al, 1999 ). Several studies have linked the KIF21B gene to neurodevelopmental and immune-related disorders, including multiple sclerosis and inflammatory conditions such as Crohn’s disease and ankylosing spondylitis ( Anderson et al, 2009 ; Asselin et al, 2020 ; Barrett et al, 2008 ; Garcia-Etxebarria et al, 2016 ; Goris et al, 2010 ; International Multiple Sclerosis Genetics Consortium (IMSGC), 2010 ; Kannan et al, 2017 ; Kreft et al, 2014 ; Li et al, 2017 ; Liu et al, 2013b ; Robinson et al, 2015 ; Yang et al, 2015 ). Kif21b knock out mice are viable but show behavioral deficits and defects in synaptic transmission ( Ghiretti et al, 2016 ; Gromova et al, 2018 ; Morikawa et al, 2018 ; Muhia et al, 2016 ).…”

Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

“…KIF21B is expressed in brain, eyes and spleen (Marszalek et al, 1999). Several studies have linked the KIF21B gene to neurodevelopmental and immune-related disorders, including multiple sclerosis and inflammatory conditions such as Crohn's disease and ankylosing spondylitis (Anderson et al, 2009;Asselin et al, 2020;Barrett et al, 2008;Garcia-Etxebarria et al, 2016;Goris et al, 2010;International Multiple Sclerosis Genetics, 2010;Kannan et al, 2017;Kreft et al, 2014;Li et al, 2017;Liu et al, 2013b;Robinson et al, 2015;Yang et al, 2015). Kif21b knock out mice are viable but show behavioral deficits and defects in synaptic transmission (Ghiretti et al, 2016;Gromova et al, 2018;Morikawa et al, 2018;Muhia et al, 2016).…”

Cytoskeletal regulation guides neuronal trafficking to effectively supply the synapse

“…Missense mutations or loss of KIF21B cause neurodevelopmental abnormalities in humans and knockout mice 77,78 , consistent with the importance of the known cellular roles of this motor in the trafficking of brain-derived neurotrophic factor (BDNF) bound to its receptor tyrosine receptor kinase B (TrkB) and the surface expression of synaptic receptors 76,77 .…”