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A novel form of PCD that impacts nodal, but not tracheal cilia

Motile cilia, in the embryonic node, drive a leftward fluid flow (termed nodal flow) that establishes the left-right axis. We identified lrm5 in a genetic screen for mouse left-right patterning mutants - the embryos exhibited disturbed situs. Mapping and sequencing revealed a novel mutation in the axonemal dynein heavy chain locus Dnah11: loss of function gives rise to immotile cilia in mice; many human primary ciliary dyskinesia (PCD) patients with DNAH11 mutations have hyper-motile cilia. To our surprise, unlike the previously characterised Dnah11iv mutant, lrm5 tracheal ciliary beat frequency (CBF) was normal. However, the number of lrm5 homozygotes at weaning was lower than Mendelian ratios would predict. Age of death analysis identified a 50% reduction in embryos between E14.5 and E15.5, consistent with death from embryonic cardiac failure. Expression analysis of early molecular markers of left-right asymmetry revealed randomised or bilateral activation of the normally left-sided Nodal Cascade. As this suggested an early, primary patterning defect, we analysed nodal flow by particle image velocimetry (PIV); rather than the wild-type leftward flow, or the absent flow in Dnah11iv , we observed a chaotic fluid flow in lrm5 nodes. We therefore assessed nodal CBF and ciliary amplitude by DIC microscopy; lrm5 cilia beat at 1.5x normal frequency, but with an abnormal motion. In summary, lrm5 is a novel form of PCD, impacting nodal but not tracheal ciliary beating. We would predict that equivalent mutations in humans might underlie situs defects and congenital heart disease in the absence of respiratory disease.

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Keynton, J., Adams, E., Riley, K. et al. A novel form of PCD that impacts nodal, but not tracheal cilia. Cilia 4 (Suppl 1), O15 (2015).

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