Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2020

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

Neil Hanchard
Kirsty Mcwalter
Marjan Weiss

Abstract

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.
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Origin Publication funded by an institution

Dates and versions

hal-03373809 , version 1 (25-11-2022)

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Laure Asselin, José Rivera Alvarez, Solveig Heide, Camille Bonnet, Peggy Tilly, et al.. Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity. Nature Communications, 2020, 11 (1), ⟨10.1038/s41467-020-16294-6⟩. ⟨hal-03373809⟩
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