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Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function
  1. Marjolein H Willemsen1,2,
  2. Wei Ba1,3,4,
  3. Willemijn M Wissink-Lindhout1,
  4. Arjan P M de Brouwer1,2,
  5. Stefan A Haas5,
  6. Melanie Bienek6,
  7. Hao Hu6,
  8. Lisenka E L M Vissers1,2,
  9. Hans van Bokhoven1,2,3,4,
  10. Vera Kalscheuer6,
  11. Nael Nadif Kasri1,2,3,4,
  12. Tjitske Kleefstra1,2
  1. 1Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
  2. 2Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Diseases, Radboud university medical center, Nijmegen, The Netherlands
  3. 3Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen, The Netherlands
  4. 4Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands
  5. 5Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany
  6. 6Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
  1. Correspondence to Dr Nael Nadif Kasri, Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen, The Netherlands; Nael.NadifKasri{at}radboudumc.nl; Dr Tjitske Kleefstra, Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disease, Radboud university medical center, Nijmegen, The Netherlands; Tjitske.Kleefstra{at}radboudumc.nl

Abstract

Introduction Kinesin superfamily (KIF) genes encode motor proteins that have fundamental roles in brain functioning, development, survival and plasticity by regulating the transport of cargo along microtubules within axons, dendrites and synapses. Mouse knockout studies support these important functions in the nervous system. The role of KIF genes in intellectual disability (ID) has so far received limited attention, although previous studies have suggested that many ID genes impinge on synaptic function.

Methods By applying next-generation sequencing (NGS) in ID patients, we identified likely pathogenic mutations in KIF4A and KIF5C. To further confirm the pathogenicity of these mutations, we performed functional studies at the level of synaptic function in primary rat hippocampal neurons.

Results and conclusions Four males from a single family with a disruptive mutation in the X-linked KIF4A (c.1489-8_1490delins10; p.?- exon skipping) showed mild to moderate ID and epilepsy. A female patient with a de novo missense mutation in KIF5C (c.11465A>C; p.(Glu237Lys)) presented with severe ID, epilepsy, microcephaly and cortical malformation. Knock-down of Kif4a in rat primary hippocampal neurons altered the balance between excitatory and inhibitory synaptic transmission, whereas the mutation in Kif5c affected its protein function at excitatory synapses. Our results suggest that mutations in KIF4A and KIF5C cause ID by tipping the balance between excitatory and inhibitory synaptic excitability.

  • KIF4A
  • KIF5C
  • intellectual disability
  • cortical malformation
  • synaptic function

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