ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Zariwala, M.A., Gee, H.Y., Kurkowiak, M., Al-Mutairi, D.A., Leigh, M.W., Hurd, T.W., Hjeij, R., Dell, S.D., Chaki, M., Dougherty, G.W., Adan, M., Spear, P.C., Esteve-Rudd, J., Loges, N.T., Rosenfeld, M., Diaz, K.A., Olbrich, H., Wolf, W.E., Sheridan, E., Batten, T.F., Halbritter, J., Porath, J.D., Kohl, S., Lovric, S., Hwang, D.Y., Pittman, J.E., Burns, K.A., Ferkol, T.W., Sagel, S.D., Olivier, K.N., Morgan, L.C., Werner, C., Raidt, J., Pennekamp, P., Sun, Z., Zhou, W., Airik, R., Natarajan, S., Allen, S.J., Amirav, I., Wieczorek, D., Landwehr, K., Nielsen, K., Schwerk, N., Sertic, J., Köhler, G., Washburn, J., Levy, S., Fan, S., Koerner-Rettberg, C., Amselem, S., Williams, D.S., Mitchell, B.J., Drummond, I.A., Otto, E.A., Omran, H., Knowles, M.R., and Hildebrandt, F.
American journal of human genetics   93(2): 336-345 (Journal)
Registered Authors
Drummond, Iain, Sun, Zhaoxia, Zhou, Weibin
MeSH Terms
  • Animals
  • Autoantigens/genetics
  • Autoantigens/metabolism
  • Axonemal Dyneins/genetics
  • Axonemal Dyneins/metabolism
  • Biomarkers/metabolism
  • Cell Cycle Proteins/genetics
  • Cell Cycle Proteins/metabolism
  • Cilia/genetics*
  • Cilia/metabolism
  • Cilia/pathology
  • Exome
  • Gene Expression Regulation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Kartagener Syndrome/genetics*
  • Kartagener Syndrome/metabolism
  • Kartagener Syndrome/pathology
  • Male
  • Microtubule-Associated Proteins/genetics
  • Microtubule-Associated Proteins/metabolism
  • Mutation
  • Pedigree
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins/genetics*
  • Proteins/metabolism
  • Rats
  • Respiratory System/metabolism*
  • Respiratory System/pathology
  • Tumor Suppressor Proteins/genetics*
  • Tumor Suppressor Proteins/metabolism
  • Xenopus laevis/genetics
  • Xenopus laevis/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism
23891469 Full text @ Am. J. Hum. Genet.

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.

Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes