Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.
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We are grateful to all individuals with primary ciliary dyskinesia (PCD) and family members for their participation, as well as Michele Manion, who founded the United States PCD Foundation. We thank the German support group “Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.” This research was supported by grants from the National Institutes of Health (NIH) to F.H. (DK068306 and DK090917), to W.Z. (DK091405), to I.A.D. (DK053093 and DK070263), to D.S.W (EY013408), and to Z.S. (DK092808-01A1). This work was supported in part by NIH grants UL1 TR000083 and UL1 TR000154 from the National Center for Advancing Translational Sciences. M.K. is supported by the project “Studies of nucleic acids and proteins—from basic to applied research,” sponsored by the International PhD Projects Programme of Foundation for Polish Science. The project is cofinanced by the European Union Regional Development Fund. D.A.M. was supported by the Department of Pathology, Faculty of Medicine, Kuwait University. M.A.Z., M.W.L., S.D.D., M.R., T.W.F., S.D.S., J.E.P., K.N.O., and M.R.K. are supported by NIH research grant 5 U54 HL096458-06, funded by the Office of the Director, and supported by the Office of Rare Diseases Research and the National Heart, Lung, and Blood Institute (NHLBI). M.A.Z. and M.R.K. are supported by NIH NHLBI grant 5 R01HL071798. H.O. is supported by the Deutsche Forschungsgemeinschaft (DFG Om 6/4 and Om 6/5, GRK1104, and SFB592), IZKF Münster, the Cell Dynamics and Disease graduate school, and project SYSCILIA from the European Community. Additional acknowledgements are provided in the Supplemental Data .
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