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ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6
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 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. © 2013 The American Society of Human Genetics.
- University of Toronto Canada
- University of Edinburgh United Kingdom
- University of North Carolina at Chapel Hill United States
- University of Duisburg-Essen Germany
- International Institute of Molecular and Cell Biology Poland
Microsoft Academic Graph classification: Ciliogenesis Cilium Centriole Primary ciliary dyskinesia medicine.disease medicine Biology Cystic kidney Zebrafish biology.organism_classification Cell biology Mutation medicine.disease_cause Motile cilium Molecular biology
[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV]Life Sciences [q-bio], [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetics(clinical), Genetics, Medizin, primary ciliary dyskinesia; ZMYND10; LRRC6, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV] Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Report, Animals, Autoantigens, Axonemal Dyneins, Biomarkers, Cell Cycle Proteins, Cilia, Cytoskeletal Proteins, Exome, Gene Expression Regulation, High-Throughput Nucleotide Sequencing, Humans, Kartagener Syndrome, Male, Microtubule-Associated Proteins, Mutation, Pedigree, Protein Binding, Protein Structure, Tertiary, Proteins, Rats, Respiratory System, Tumor Suppressor Proteins, Xenopus laevis, Zebrafish, Genetics (clinical)
[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV]Life Sciences [q-bio], [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetics(clinical), Genetics, Medizin, primary ciliary dyskinesia; ZMYND10; LRRC6, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV] Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Report, Animals, Autoantigens, Axonemal Dyneins, Biomarkers, Cell Cycle Proteins, Cilia, Cytoskeletal Proteins, Exome, Gene Expression Regulation, High-Throughput Nucleotide Sequencing, Humans, Kartagener Syndrome, Male, Microtubule-Associated Proteins, Mutation, Pedigree, Protein Binding, Protein Structure, Tertiary, Proteins, Rats, Respiratory System, Tumor Suppressor Proteins, Xenopus laevis, Zebrafish, Genetics (clinical)
Microsoft Academic Graph classification: Ciliogenesis Cilium Centriole Primary ciliary dyskinesia medicine.disease medicine Biology Cystic kidney Zebrafish biology.organism_classification Cell biology Mutation medicine.disease_cause Motile cilium Molecular biology
3214
1. Leigh, M.W., Pittman, J.E., Carson, J.L., Ferkol, T.W., Dell, S.D., Davis, S.D., Knowles, M.R., and Zariwala, M.A. (2009). Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet. Med. 11, 473-487. [OpenAIRE]
2. Noone, P.G., Leigh, M.W., Sannuti, A., Minnix, S.L., Carson, J.L., Hazucha, M., Zariwala, M.A., and Knowles, M.R. (2004). Primary ciliary dyskinesia: diagnostic and phenotypic features. Am. J. Respir. Crit. Care Med. 169, 459-467.
3. Zariwala, M.A., Knowles, M.R., and Omran, H. (2007). Genetic defects in ciliary structure and function. Annu. Rev. Physiol. 69, 423-450.
4. Kennedy, M.P., Omran, H., Leigh, M.W., Dell, S., Morgan, L., Molina, P.L., Robinson, B.V., Minnix, S.L., Olbrich, H., Severin, T., et al. (2007). Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation 115, 2814-2821.
5. Schwabe, G.C., Hoffmann, K., Loges, N.T., Birker, D., Rossier, C., de Santi, M.M., Olbrich, H., Fliegauf, M., Failly, M., Liebers, U., et al. (2008). Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused by DNAH11 mutations. Hum. Mutat. 29, 289-298.
6. Knowles, M.R., Leigh, M.W., Carson, J.L., Davis, S.D., Dell, S.D., Ferkol, T.W., Olivier, K.N., Sagel, S.D., Rosenfeld, M., Burns, K.A., et al.; Genetic Disorders of Mucociliary Clearance Consortium. (2012). Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. Thorax 67, 433-441.
7. Becker-Heck, A., Zohn, I.E., Okabe, N., Pollock, A., Lenhart, K.B., Sullivan-Brown, J., McSheene, J., Loges, N.T., Olbrich, H., Haeffner, K., et al. (2011). The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nat. Genet. 43, 79-84.
8. Merveille, A.C., Davis, E.E., Becker-Heck, A., Legendre, M., Amirav, I., Bataille, G., Belmont, J., Beydon, N., Billen, F., Cle´ment, A., et al. (2011). CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat. Genet. 43, 72-78.
9. Loges, N.T., Olbrich, H., Fenske, L., Mussaffi, H., Horvath, J., Fliegauf, M., Kuhl, H., Baktai, G., Peterffy, E., Chodhari, R., et al. (2008). DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm. Am. J. Hum. Genet. 83, 547-558. [OpenAIRE]
10. Wirschell, M., Olbrich, H., Werner, C., Tritschler, D., Bower, R., Sale, W.S., Loges, N.T., Pennekamp, P., Lindberg, S., Stenram, U., et al. (2013). The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. Nat. Genet. 45, 262-268.
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- National Institutes of Health (NIH)
- 5U54HL096458-14
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
- National Institutes of Health (NIH)
- 1RC4DK090917-01
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
- Wellcome Trust (WT)
- National Institutes of Health (NIH)
- 5R01DK068306-17
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
- University of Toronto Canada
- University of Edinburgh United Kingdom
- University of North Carolina at Chapel Hill United States
- University of Duisburg-Essen Germany
- International Institute of Molecular and Cell Biology Poland
- Northeastern University United States
- Department of Pediatrics University of Maryland School of Medicine United States
- Yale University United States
- University of Michigan–Flint United States
- University of Leeds United Kingdom
- Washington State University United States
- Bar-Ilan University Israel
- Polish Academy of Learning Poland
- National Institute of Allergy and Infectious Diseases United States
- University of Copenhagen Denmark
- University of Colorado Denver United States
- University of Münster Germany
- St James's University Hospital United Kingdom
- University of Mary United States
- University of Michigan
- UNIVERSITY OF NORTH CAROLINA
- Kiel University Germany
- Inserm France
- University of California, Los Angeles United States
- University of Michigan–Ann Arbor United States
- Northwestern University United States
- Sorbonne Paris Cité France
- Massachusetts General Hospital United States
- Concord Repatriation General Hospital Australia
- Howard Hughes Medical Institute United States
- University of Washington United States
- University of Zagreb Croatia
- Bethel University United States
- UNIV OF NORTH CAROLINA CHAPEL HILL
- HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY United States
- Harvard Medical School United States
- Department of Genetics Harvard Medical School Harvard University United States
- Copenhagen University Hospital Denmark
- CHILDRENS HOSPITAL BOSTON
- HudsonAlpha Institute for Biotechnology United States
- UNIVERSITY OF WASHINGTON United States
- Seattle Children's Hospital United States
- Northwestern State University United States
- National Institutes of Health United States
- Boston Children's Hospital United States
- Kuwait University Kuwait
- Harvard Medical School United States
- University of Colorado Denver
- Evangelisches Krankenhaus Bielefeld Germany
- Ruhr University Bochum Germany
- Harvard University United States
- Polish Academy of Sciences Poland
- University of Colorado System United States
- University Hospital Münster Germany
- Northwestern University United States
- University of California System United States
- Leeds Teaching Hospitals NHS Trust United Kingdom
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. © 2013 The American Society of Human Genetics.