No Evidence for Cardiac Dysfunction in Kif6 Mutant Mice

PLOS ONE, Dec 2019

A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice. Kif6 mutant mice were generated and verified. Cardiac function was assessed by serial echocardiography at baseline, after ageing and after exercise. Lipid levels were also measured. No discernable adverse lipid or cardiac phenotype was detected in Kif6 mutant mice. These data suggest that dysfunction of Kif6 is linked to other more complex biological/biochemical parameters or is unlikely to be of material consequence in cardiac function.

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No Evidence for Cardiac Dysfunction in Kif6 Mutant Mice

Citation: Hameed A, Bennett E, Ciani B, Hoebers LPC, Milner R, et al. ( No Evidence for Cardiac Dysfunction in Kif6 Mutant Mice Abdul Hameed 0 Ellen Bennett 0 Barbara Ciani 0 Loes P. C. Hoebers 0 Roy Milner 0 Allan Lawrie 0 Sheila E. Francis 0 Andrew J. Grierson 0 Katriina Aalto-Setala, University of Tampere, Finland 0 1 Department of Cardiovascular Science, Medical School, University of Sheffield , Sheffield , United Kingdom , 2 Sheffield Institute for Translational Neuroscience, University of Sheffield , Sheffield , United Kingdom , 3 Department of Chemistry, University of Sheffield , Sheffield , United Kingdom A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice. Kif6 mutant mice were generated and verified. Cardiac function was assessed by serial echocardiography at baseline, after ageing and after exercise. Lipid levels were also measured. No discernable adverse lipid or cardiac phenotype was detected in Kif6 mutant mice. These data suggest that dysfunction of Kif6 is linked to other more complex biological/biochemical parameters or is unlikely to be of material consequence in cardiac function. - Funding: This study was supported by the Research and Innovation Fund, University of Sheffield. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. There has been considerable debate within the cardiovascular community regarding the role of kinesin-like protein 6 (Kif6) in coronary artery disease. Initial reports using a candidate gene based approach in several atherosclerosis population cohorts observed an increase risk of adverse coronary events in carriers of the rs20455 C variant in the KIF6 gene which leads to a Trp719Arg substitution in the Kif6 protein [1,2,3,4]. These findings were controversial and refuted by a large GWAS metaanalysis using 19 case-control studies [5] where cases were defined either by a history of prior myocardial infarction and/or the presence of coronary artery disease at angiography. Furthermore no association between the kif6 variant and coronary events was observed in the most recent large meta-analysis [6]. However, evidence from interventional randomized controlled trials (RCTs) with statins associated carriage of this genotype with a greater clinical response to statin therapy [7,8,9,10]. As a clinical test based on KIF6 genotype was already on the market, the utility and clinical significance of this was in doubt [11,12]. More recently, retrospective analyses from several large independent RCTs [13,14,15,16,17] have not observed an increased risk of adverse vascular events or an attenuated response to statin therapy amongst Kif6 719Arg carriers. In an attempt to reconcile these discrepant findings, Ference et al hypothesized that the rs20455 C variant in the KIF6 gene may influence LDL levels. By performing a regression meta-analysis involving almost 145,000 patients, they reported that carriers demonstrated greater reductions in LDL, when treated with statins and consequently greater reduction in clinical events when compared to non-carriers [6]. Kif6 is a member of the Kinesin 9 superfamily but the precise molecular function of Kif6 is not known. It is likely to play a role in the cellular transport of proteins along microtubules [18,19] and could plausibly be involved in cellular transport in the cardiovascular system. Hitherto, all studies have focused on investigating polymorphism in the KIF6 gene within the context of coronary artery disease yet to our knowledge there has been no investigation (experimental or clinical) into its function (if any) on heart function. We hypothesised that if loss of Kif6 function was associated with cardiovascular disease, then mice with a deleterious mutation in the Kif6 motor domain may exhibit defects in cardiac physiology. Therefore, we identified mice with an N-ethyl-N-nitrosourea (ENU) induced mutation in the Kif6 motor, and investigated the structural and functional cardiac phenotypes by high frequency transthoracic echocardiography. Kif6 mutant mice were obtained from the RIKEN Bioresource Centre (Japan, RBRC03194), backcrossed 5 generations to C57BL/6 and classed as incipient congenics. The likelihood that a phenotype would arise because of a confounding mutation in the RIKEN library is statistically slim (p,0.002) [20]. RT-PCR and Western blot analysis of Kif6 expression was performed according to standard methods [21]. A rabbit polyclonal antibody (Kif6 C165) was generated using a peptide containing 20 C-terminal amino acids of human Kif6 as an immunogen. Specificity of the antibody was demonstra (...truncated)


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Abdul Hameed, Ellen Bennett, Barbara Ciani, Loes P. C. Hoebers, Roy Milner, Allan Lawrie, Sheila E. Francis, Andrew J. Grierson. No Evidence for Cardiac Dysfunction in Kif6 Mutant Mice, PLOS ONE, 2013, Volume 8, Issue 1, DOI: 10.1371/journal.pone.0054636