title: Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Diseases, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen, The Netherlands Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Wei
authors.initials: W
authors.lastname: Ba
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Willemijn M
authors.initials: WM
authors.lastname: Wissink-Lindhout
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Diseases, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bienek
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Diseases, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Diseases, Radboud university medical center, Nijmegen, The Netherlands Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen, The Netherlands Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Kalscheuer
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Diseases, Radboud university medical center, Nijmegen, The Netherlands Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen, The Netherlands Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Nael
authors.initials: N
authors.lastname: Nadif Kasri
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Diseases, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
mesh_terms: D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D016547:Kinesins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009474:Neurons / Q000502:physiology; D010375:Pedigree; D061251:Primary Cell Culture; D051381:Rats; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission
chemical_list: C484228:KIF4A protein, human; C514435:KIF5C protein, human; D016547:Kinesins
keywords: KIF4A; KIF5C; cortical malformation; intellectual disability; synaptic function