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XB-ART-55506
PLoS Genet January 1, 2018; 14 (11): e1007817.

Mutations in Kinesin family member 6 reveal specific role in ependymal cell ciliogenesis and human neurological development.

Konjikusic MJ , Yeetong P , Boswell CW , Lee C , Roberson EC , Ittiwut R , Suphapeetiporn K , Ciruna B , Gurnett CA , Wallingford JB , Shotelersuk V , Gray RS .


Abstract
Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Member 6 (KIF6) gene in a child displaying neurodevelopmental defects and intellectual disability. To test the pathogenicity of this novel human KIF6 mutation we engineered an analogous C-terminal truncating mutation in mouse. These mutant mice display severe, postnatal-onset hydrocephalus. We generated a Kif6-LacZ transgenic mouse strain and report expression specifically and uniquely within the ependymal cells (ECs) of the brain, without labeling other multiciliated mouse tissues. Analysis of Kif6 mutant mice with scanning electron microscopy (SEM) and immunofluorescence (IF) revealed specific defects in the formation of EC cilia, without obvious effect of cilia of other multiciliated tissues. Dilation of the ventricular system and defects in the formation of EC cilia were also observed in adult kif6 mutant zebrafish. Finally, we report Kif6-GFP localization at the axoneme and basal bodies of multi-ciliated cells (MCCs) of the mucociliary Xenopus epidermis. Overall, this work describes the first clinically-defined KIF6 homozygous null mutation in human and defines KIF6 as a conserved mediator of neurological development with a specific role for EC ciliogenesis in vertebrates.

PubMed ID: 30475797
PMC ID: PMC6307780
Article link: PLoS Genet
Grant support: [+]

Species referenced: Xenopus
Genes referenced: arl13b cdkn1a cdknx cetn4 kif6 lamtor2 prom1
GO keywords: cilium

Disease Ontology terms: primary ciliary dyskinesia

Article Images: [+] show captions
References [+] :
Assimes, Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies. 2010, Pubmed