Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function

J Med Genet. 2014 Jul;51(7):487-94. doi: 10.1136/jmedgenet-2013-102182.

Marjolein H Willemsen ¹, Wei Ba ², Willemijn M Wissink-Lindhout ³, Arjan P M de Brouwer ¹, Stefan A Haas ⁴, Melanie Bienek ⁵, Hao Hu ⁵, Lisenka E L M Vissers ¹, Hans van Bokhoven ⁶, Vera Kalscheuer ⁵, Nael Nadif Kasri ⁶, Tjitske Kleefstra ¹

Affiliations

1 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.
2 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.
3 Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
4 Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
5 Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
6 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.

PMID: 24812067 DOI: 10.1136/jmedgenet-2013-102182

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.

Keywords

KIF4A; KIF5C; cortical malformation; intellectual disability; synaptic function.

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