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.