ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

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 rec...

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Published in:American journal of human genetics 2013-08, Vol.93 (2), p.336-345
Main Authors: Zariwala, Maimoona A., Gee, Heon Yung, Kurkowiak, Małgorzata, Al-Mutairi, Dalal A., Leigh, Margaret W., Hurd, Toby W., Hjeij, Rim, Dell, Sharon D., Chaki, Moumita, Dougherty, Gerard W., Adan, Mohamed, Spear, Philip C., Esteve-Rudd, Julian, Loges, Niki T., Rosenfeld, Margaret, Diaz, Katrina A., Olbrich, Heike, Wolf, Whitney E., Sheridan, Eamonn, Batten, Trevor F.C., Halbritter, Jan, Porath, Jonathan D., Kohl, Stefan, Lovric, Svjetlana, Hwang, Daw-Yang, Pittman, Jessica E., Burns, Kimberlie A., Ferkol, Thomas W., Sagel, Scott D., Olivier, Kenneth N., Morgan, Lucy C., Werner, Claudius, Raidt, Johanna, Pennekamp, Petra, Sun, Zhaoxia, Zhou, Weibin, Airik, Rannar, Natarajan, Sivakumar, Allen, Susan J., Amirav, Israel, Wieczorek, Dagmar, Landwehr, Kerstin, Nielsen, Kim, Schwerk, Nicolaus, Sertic, Jadranka, Köhler, Gabriele, Washburn, Joseph, Levy, Shawn, Fan, Shuling, Koerner-Rettberg, Cordula, Amselem, Serge, Williams, David S., Mitchell, Brian J., Drummond, Iain A., Otto, Edgar A., Omran, Heymut, Knowles, Michael R., Hildebrandt, Friedhelm
Format: Article
Language:English
Subjects:
Animals
Autoantigens - genetics
Autoantigens - metabolism
Axonemal Dyneins - genetics
Axonemal Dyneins - metabolism
Biomarkers
Biomarkers - metabolism
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cilia - genetics
Cilia - metabolism
Cilia - pathology
Cytoplasm
Exome
Gene Expression Regulation
Genetic disorders
Genetics
High-Throughput Nucleotide Sequencing
Human health and pathology
Humans
Kartagener Syndrome - genetics
Kartagener Syndrome - metabolism
Kartagener Syndrome - pathology
Life Sciences
Male
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - metabolism
Mutation
Pedigree
Protein Binding
Protein Structure, Tertiary
Proteins
Proteins - genetics
Proteins - metabolism
Pulmonology and respiratory tract
Rats
Respiratory System - metabolism
Respiratory System - pathology
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Xenopus laevis - genetics
Xenopus laevis - metabolism
Zebrafish
Zebrafish - genetics
Zebrafish - metabolism
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Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2013.06.007