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Involvement of the Kinesin Family Members KIF4A and KIF5C In

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Involvement of the Kinesin Family Members KIF4A and KIF5C In Downloaded from http://jmg.bmj.com/ on March 10, 2015 - Published by group.bmj.com Cognitive and behavioural genetics ORIGINAL ARTICLE Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic Editor’s choice Scan to access more free content function Marjolein H Willemsen,1,2 Wei Ba,1,3,4 Willemijn M Wissink-Lindhout,1 Arjan P M de Brouwer,1,2 Stefan A Haas,5 Melanie Bienek,6 Hao Hu,6 Lisenka E L M Vissers,1,2 Hans van Bokhoven,1,2,3,4 Vera Kalscheuer,6 Nael Nadif Kasri,1,2,3,4 Tjitske Kleefstra1,2 For numbered affiliations see ABSTRACT genes in the development and functioning of the end of article. Introduction Kinesin superfamily (KIF) genes encode nervous system. Mice with homozygous knockout Kif1a 1b 2a 3a 3b 4a 5a 5b Correspondence to motor proteins that have fundamental roles in brain mutations in , , , , , , and Dr Nael Nadif Kasri, functioning, development, survival and plasticity by show various neurological phenotypes including Department of Cognitive regulating the transport of cargo along microtubules structural brain anomalies, decreased brain size, Neuroscience, Radboud within axons, dendrites and synapses. Mouse knockout loss of neurons, reduced rate of neuronal apoptosis university medical center, studies support these important functions in the nervous and perinatal lethality due to neurological pro- Nijmegen, The Netherlands; 4–12 Nael.NadifKasri@radboudumc. system. The role of KIF genes in intellectual disability (ID) blems. The embryonic lethality of knockout nl; has so far received limited attention, although previous mice for Kif2a, Kif3a and 3b, and Kif5b suggest Dr Tjitske Kleefstra, studies have suggested that many ID genes impinge on that these Kif genes have an important function in Department of Human synaptic function. general developmental processes as well.57813 Genetics, Nijmegen Centre for Methods By applying next-generation sequencing Overexpression of Kif17 in mice resulted in Molecular Life Sciences and 14 Institute for Genetic and (NGS) in ID patients, we identified likely pathogenic enhanced spatial learning. Conditional knockout Metabolic Disease, Radboud mutations in KIF4A and KIF5C. To further confirm the of KIF5A in mice led to epileptic phenotypes.15 university medical center, pathogenicity of these mutations, we performed Several KIF genes have previously been impli- Nijmegen, The Netherlands; functional studies at the level of synaptic function in cated in the pathogenesis of neurodegenerative and Tjitske.Kleefstra@radboudumc. nl primary rat hippocampal neurons. neurodevelopmental disorders in humans (table 1). Results and conclusions Four males from a single Only a handful of previous reports relate to MHW, WB, NNK and TK family with a disruptive mutation in the X-linked KIF4A mutations in KIF genes to intellectual disability contributed equally. (c.1489-8_1490delins10; p.?- exon skipping) showed (ID). Putoux et al21 identified homozygous muta- KIF7 Received 10 December 2013 mild to moderate ID and epilepsy. A female patient with tions in (MIM 611254) in patients with acro- Revised 7 April 2014 a de novo missense mutation in KIF5C (c.11465A>C; callosal syndrome (MIM 200990) and Accepted 8 April 2014 p.(Glu237Lys)) presented with severe ID, epilepsy, hydrolethalus syndrome (MIM 614120), and Published Online First microcephaly and cortical malformation. Knock-down of homozygous mutations in the same gene were also 8 May 2014 Kif4a in rat primary hippocampal neurons altered the found in patients with Joubert syndrome 12 (MIM balance between excitatory and inhibitory synaptic 200990).22 In these ciliary disorders ID is part of transmission, whereas the mutation in Kif5c affected its the phenotype. Najmabadi et al23 identified a protein function at excitatory synapses. Our results homozygous missense mutation in KIF7 by targeted suggest that mutations in KIF4A and KIF5C cause ID by sequencing of exons from homozygous linkage tipping the balance between excitatory and inhibitory intervals in a consanguineous family with ID, club- synaptic excitability. feet, cataract, hearing loss and midface hypoplasia. More recently, the first dominant de novo missense mutation in a KIF gene (KIF1A) was found in a INTRODUCTION patient with non-syndromic ID.17 Recently, Poirier Kinesin superfamily proteins (KIF) are motor pro- et al19 reported the identification of mutations in teins involved in the movement of various cargoes KIF2A and KIF5C in patients with malformations along the microtubules, including vesicles, orga- of cortical development (MCD). These patients nelles, protein complexes, mRNAs and chromo- presented with ID as well. – somes.1 4 KIF proteins act together with motor Here, we report the identification of a mutation proteins from the dynein and myosin superfamilies. in KIF4A (MIM 300521) in an X-linked ID family, These molecular motors are expected to have fun- presenting with mild to moderate ID and epilepsy, damental roles in several processes in the brain, and a mutation in KIF5C (MIM 604593) in a including neuronal functioning, development, sur- sporadic patient with severe ID, microcephaly, epi- To cite: Willemsen MH, vival and plasticity, by regulating the anterograde lepsy and cortical malformation. Additionally, we Ba W, Wissink- and retrograde transport within the axons, den- studied the effects on synaptic function of these – Lindhout WM, et al. J Med drites and synapses of neurons.1 4 Studies in mouse KIF genes using a knockdown system in rat primary – Genet 2014;51:487 494. models support these essential functions of KIF neurons. Willemsen MH, et al. J Med Genet 2014;51:487–494. doi:10.1136/jmedgenet-2013-102182 487 Downloaded from http://jmg.bmj.com/ on March 10, 2015 - Published by group.bmj.com Cognitive and behavioural genetics Table 1 Kinesin superfamily (KIF) genes implicated in neurodegenerative and neurodevelopmental diseases in humans KIF gene Disease Inheritance Reference KIF1A (MIM 601255) Hereditary spastic paraplegia type 30 AR 41617 (MIM 610358) AR Hereditary sensory neuropathy, type IIC AD (MIM 614213) Non-syndromic ID KIF1B (MIM 605995) Charcot-Marie-Tooth disease , type 2A1 AD 11 18 (MIM 118210) susceptibility locus Multiple sclerosis (MIM 126200) KIF2A (MIM 602591) MCD AD 19 KIF5A (MIM 602821) Hereditary spastic paraplegia type 10 AD 420 (MIM 604187) KIF5C (MIM 604593) MCD AD 19 – KIF7 (MIM 611254) Acrocallosal syndrome (MIM 200990) AR 21 23 Hydrolethalus syndrome (MIM 614120) AR Joubert syndrome 12 (MIM 200990) AR Syndromic ID AR KIF11 (MIM 148760) Microcephaly with or without chorioretinopathy, lymphedema, AD 24 or mental retardation (MIM 152950) KIF21A (MIM 608283) Congenital opthalmoplegia (MIM 135700) AD 25 AD, autosomal dominant; AR, autosomal recessive; ID, intellectual disability; MCD, malformations of cortical development. METHODS that is not homologous to any known genes was used as transfection Patient ascertainment efficiency detector and a negative control. Each siRNA was tested in Family 1 was included in a larger project involving sequencing hippocampal neurons and validated using quantitative PCR. of all exons of the X-chromosome in >200 families with Primary hippocampal neurons were prepared as described previ- X-linked ID. For each family, DNA from one affected male was ously27 and transfected with siRNAs at 6 days in vitro (DIV). Three subjected to targeted enrichment of all X-chromosome-specific days later, whole-cell recordings were obtained from transfected exons followed by next-generation sequencing (NGS). The neurons. In experiments in which we examined the role of KIF5C enriched and sequenced exons encompassed 99.2% of the 7759 wild type (WT) and KIF5C-E237 K on miniature excitatory postsy- disease-causing X-chromosomal changes listed in the Human naptic currents (mEPSCs), primary hippocampal neurons were elec- Gene Mutation Database (HGMD, update April 2011). Variants troporated immediately after dissociation using the Amaxa were filtered against dbSNP135, control populations (185 Nucleofector device (Amaxa GmbH). 3 μg total of green fluorescent genomes from the 1000 Genomes Project Consortium; http:// protein (GFP), KIF5C-WT and KIF5C-E237 K plasmids was used www.1000genomes.org/data, 200 Danish exomes, the NHLBI per electroporation. Whole-cell recordings were conducted from Exome Sequencing Project (ESP, freeze 5400)) as well as an transfected neurons in every group. The YFP-KIF5c (KIF5c-WT) in-house database (Kalscheuer et al, personal communication). construct was a gift from Dr A Stephenson. The KIF5C mutant Variants with a minor allele frequency of ≥0.5% were excluded. (KIF5C-E237 K) was generated by introducing a point mutation In patient 2, we performed family based whole-exome (E237 K) using the Quick Change system (Stratagene). sequencing as previously described by de Ligt et al.26 Measurement of mEPSCs and measurement of miniature Confirmation of mutations and segregation analysis were inhibitory postsynaptic currents in rat primary hippocampal done by Sanger sequencing. neurons Whole-cell voltage-clamp recordings were performed from Kif4a RNA expression studies in cell-lines of patients from family control neurons or neurons transfected with siRNAs against 1 with a mutation in KIF4A or cDNA-expressing KIF5C-WT/E237 K at holding potential of − fi fl RNA was isolated from a cell-line from an affected family 60 mV in arti cial cerebro-spinal uid (ACSF) containing member and a healthy control person. Primers for PCR analysis 2.5 mM CaCl2 and 1.2 mM MgCl2 at 30°C. mEPSCs were μ were designed at exon 13/14 and exon 16/17 boundaries and recorded in the presence of 1 M tetrodotoxine (TTX) and cDNA was synthesised. Sequencing of the PCR product in an 0.1 mM picrotoxin. Miniature inhibitory postsynaptic currents μ μ affected family member and the healthy control person was per- (mIPSC) were recorded in the presence of 1 MTTX,10 M6- μ formed to confirm skipping of exon 15 in the patients. cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 100 M ((2R)- amino-5-phosphonovaleric acid (APV). Five to 10 min of record- ings were analysed from each cell using the Mini Analysis Program siRNAs, DNA constructs, hippocampal neurons and (Synaptosoft) using 8 pA as a threshold to detect an event.
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