TY - JOUR
T1 - Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity
AU - Asselin, Laure
AU - Rivera Alvarez, José
AU - Heide, Solveig
AU - Bonnet, Camille S.
AU - Tilly, Peggy
AU - Vitet, Hélène
AU - Weber, Chantal
AU - Bacino, Carlos A.
AU - Baranaño, Kristin
AU - Chassevent, Anna
AU - Dameron, Amy
AU - Faivre, Laurence
AU - Hanchard, Neil A.
AU - Mahida, Sonal
AU - McWalter, Kirsty
AU - Mignot, Cyril
AU - Nava, Caroline
AU - Rastetter, Agnès
AU - Streff, Haley
AU - Thauvin-Robinet, Christel
AU - Weiss, Marjan M.
AU - Zapata, Gladys
AU - Zwijnenburg, Petra J.G.
AU - Saudou, Frédéric
AU - Depienne, Christel
AU - Golzio, Christelle
AU - Héron, Delphine
AU - Godin, Juliette D.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-020-16294-6
DO - 10.1038/s41467-020-16294-6
M3 - Article
C2 - 32415109
AN - SCOPUS:85084741293
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2441
ER -