例如:"lncRNA", "apoptosis", "WRKY"

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

Nat Commun. 2020 May 15;11(1):2441
Laure Asselin 1 , José Rivera Alvarez 1 , Solveig Heide 2 , Camille S Bonnet 1 , Peggy Tilly 1 , Hélène Vitet 3 , Chantal Weber 1 , Carlos A Bacino 4 , Kristin Baranaño 5 , Anna Chassevent 5 , Amy Dameron 6 , Laurence Faivre 7 , Neil A Hanchard 8 , Sonal Mahida 9 , Kirsty McWalter 6 , Cyril Mignot 10 , Caroline Nava 10 , Agnès Rastetter 10 , Haley Streff 4 , Christel Thauvin-Robinet 11 , Marjan M Weiss 12 , Gladys Zapata 4 , Petra J G Zwijnenburg 12 , Frédéric Saudou 3 , Christel Depienne 13 , Christelle Golzio 1 , Delphine Héron 2 , Juliette D Godin 14
Laure Asselin 1 , José Rivera Alvarez 1 , Solveig Heide 2 , Camille S Bonnet 1 , Peggy Tilly 1 , Hélène Vitet 3 , Chantal Weber 1 , Carlos A Bacino 4 , Kristin Baranaño 5 , Anna Chassevent 5 , Amy Dameron 6 , Laurence Faivre 7 , Neil A Hanchard 8 , Sonal Mahida 9 , Kirsty McWalter 6 , Cyril Mignot 10 , Caroline Nava 10 , Agnès Rastetter 10 , Haley Streff 4 , Christel Thauvin-Robinet 11 , Marjan M Weiss 12 , Gladys Zapata 4 , Petra J G Zwijnenburg 12 , Frédéric Saudou 3 , Christel Depienne 13 , Christelle Golzio 1 , Delphine Héron 2 , Juliette D Godin 14
+ et al

[No authors listed]

Author information
  • 1 Université de Strasbourg, Strasbourg, France.
  • 2 Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Paris, France.
  • 3 Univ. Grenoble Alpes, INSERM, U1216, CHU Grenoble Alpes, Grenoble Institut Neuroscience, Grenoble, France.
  • 4 Texas Children's Hospital, Houston, TX, USA.
  • 5 Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, 21205, USA.
  • 6 GeneDx, Gaithersburg, MD, 20877, USA.
  • 7 Equipe GAD, INSERM LNC UMR 1231, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
  • 8 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 9 Department of Neurology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • 10 INSERM, U 1127, CNRS UMR 7225, Faculté de Médecine de Sorbonne Université, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
  • 11 Centre de Référence Déficiences Intellectuelles de Causes Rares, Centre Hospitalier Universitaire Dijon, Dijon, France.
  • 12 Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • 13 Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
  • 14 Université de Strasbourg, Strasbourg, France. godin@igbmc.fr.

摘要


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.