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

Laure Asselin, José Rivera Alvarez, Solveig Heide, Camille S. Bonnet, Peggy Tilly, Hélène Vitet, Chantal Weber, Carlos A. Bacino, Kristin Baranaño, Anna Chassevent, Amy Dameron, Laurence Faivre, Neil A. Hanchard, Sonal Mahida, Kirsty McWalter, Cyril Mignot, Caroline Nava, Agnès Rastetter, Haley Streff, Christel Thauvin-Robinet, Marjan M. Weiss, Gladys Zapata, Petra J. G. Zwijnenburg, Frédéric Saudou, Christel Depienne, Christelle Golzio, Delphine Héron and Juliette D. Godin ()
Additional contact information
Laure Asselin: Institut de Génétique et de Biologie Moléculaire et Cellulaire
José Rivera Alvarez: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Solveig Heide: Hôpital de la Pitié-Salpêtrière
Camille S. Bonnet: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Peggy Tilly: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Hélène Vitet: Univ. Grenoble Alpes, INSERM, U1216, CHU Grenoble Alpes, Grenoble Institut Neuroscience
Chantal Weber: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Carlos A. Bacino: Baylor College of Medicine
Kristin Baranaño: Kennedy Krieger Institute
Anna Chassevent: Kennedy Krieger Institute
Amy Dameron: GeneDx
Laurence Faivre: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon et Université de Bourgogne
Neil A. Hanchard: Baylor College of Medicine
Sonal Mahida: Boston Children’s Hospital
Kirsty McWalter: GeneDx
Cyril Mignot: Hôpital de la Pitié-Salpêtrière
Caroline Nava: Hôpital de la Pitié-Salpêtrière
Agnès Rastetter: Faculté de Médecine de Sorbonne Université, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM
Haley Streff: Baylor College of Medicine
Christel Thauvin-Robinet: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon et Université de Bourgogne
Marjan M. Weiss: Vrije Universiteit Amsterdam
Gladys Zapata: Texas Children’s Hospital
Petra J. G. Zwijnenburg: Vrije Universiteit Amsterdam
Frédéric Saudou: Univ. Grenoble Alpes, INSERM, U1216, CHU Grenoble Alpes, Grenoble Institut Neuroscience
Christel Depienne: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Christelle Golzio: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Delphine Héron: Hôpital de la Pitié-Salpêtrière
Juliette D. Godin: Institut de Génétique et de Biologie Moléculaire et Cellulaire

Nature Communications, 2020, vol. 11, issue 1, 1-18

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.

Date: 2020
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DOI: 10.1038/s41467-020-16294-6

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