RT Journal Article SR Electronic T1 Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 487 OP 494 DO 10.1136/jmedgenet-2013-102182 VO 51 IS 7 A1 Marjolein H Willemsen A1 Wei Ba A1 Willemijn M Wissink-Lindhout A1 Arjan P M de Brouwer A1 Stefan A Haas A1 Melanie Bienek A1 Hao Hu A1 Lisenka E L M Vissers A1 Hans van Bokhoven A1 Vera Kalscheuer A1 Nael Nadif Kasri A1 Tjitske Kleefstra YR 2014 UL http://jmg.bmj.com/content/51/7/487.abstract AB 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.