Journal Article

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

Bacino, Carlos A., Tilly, Peggy, Golzio, Christelle, Zwijnenburg, Petra J. G., Héron, Delphine, Rastetter, Agnès, Chassevent, Anna, Nava, Caroline, Weber, Chantal, Bonnet, Camille S., Thauvin-Robinet, Christel, Dameron, Amy, Weiss, Marjan M., Mignot, Cyril, Heide, Solveig, Baranaño, Kristin, Vitet, Hélène, Streff, Haley, Depienne, Christel, Hanchard, Neil A., Zapata, Gladys, Rivera Alvarez, José, Saudou, Frédéric, Faivre, Laurence, McWalter, Kirsty, Godin, Juliette D., Mahida, Sonal, Asselin, Laure

2020

Overview

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. Kinesins regulate intracellular transport and microtubule dynamics. Here, the authors show that KIF21B variants in humans associate with corpus callosum agenesis and microcephaly. Using mice and zebrafish, they showed the cellular mechanisms altered by the missense KIF21B variants.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/109 / 13/31 / 13/51 / 14/19 / 14/63 / 38/23 / 38/88 / 42/35 / 631/378/2571/1696 / 64/116 / 64/60 / 692/617/375/366 / 82/80 / Abnormalities / Animals / Attenuation / Axons - metabolism / Cell migration / Cell Movement / Cell Proliferation / Cerebral Cortex - embryology / Cerebral Cortex - pathology / Cerebral Cortex - physiopathology / Corpus callosum / Deregulation / Development Biology / Disorders / Embryology and Organogenesis / Female / Gene Expression Regulation, Developmental / Haploinsufficiency / HEK293 Cells / Humanities and Social Sciences / Humans / Intracellular / Kinesin / Kinesin - genetics / Life Sciences / Male / Mice / Microcephaly / Microencephaly / Motor Activity / mRNA turnover / multidisciplinary / Mutation / Mutation - genetics / Mutation, Missense - genetics / Nerve Net - pathology / Nerve Net - physiopathology / Neural networks / Neurobiology / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Neurodevelopmental Disorders - physiopathology / Neurons - metabolism / Neurons and Cognition / Nonsense mutation / Nonsense-mediated mRNA decay / Organ Size / Organogenesis - genetics / Pathogenicity / Pathogens / Pedigree / Protein transport / Reproduction (copying) / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Transport / Zebrafish / Zebrafish - anatomy & histology / Zebrafish - genetics