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

Willemsen, M. H., Ba, W., Wissink-Lindhout, W. M., de Brouwer, A. P., Haas, S. A., Bienek, M., et al. (2014). Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function. Journal of Medical Genetics, 51(7), 487-494. doi:10.1136/jmedgenet-2013-102182.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-1F40-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-1F41-A
Genre: Journal Article

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 Creators:
Willemsen, M. H., Author
Ba, W., Author
Wissink-Lindhout, W. M., Author
de Brouwer, A. P., Author
Haas, S. A.1, Author              
Bienek, M., Author
Hu, H., Author
Vissers, L. E., Author
van Bokhoven, H., Author
Kalscheuer, V.2, Author              
Nadif Kasri, N., Author
Kleefstra, T., Author
Affiliations:
1Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479640              
2Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

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 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.

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Language(s): eng - English
 Dates: 2014-05-082014-07
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1136/jmedgenet-2013-102182
ISSN: 1468-6244 (Electronic)0022-2593 (Print)
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Title: Journal of Medical Genetics
Source Genre: Journal
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Publ. Info: London : British Medical Association
Pages: - Volume / Issue: 51 (7) Sequence Number: - Start / End Page: 487 - 494 Identifier: ISSN: 0022-2593
CoNE: https://pure.mpg.de/cone/journals/resource/954925415940_2