ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Maimoona A. Zariwala (1) , Heon Yung Gee (2) , Małgorzata Kurkowiak (3, 4, 5) , Dalal A. Al-Mutairi (6, 7) , Margaret W. Leigh (1) , Toby W. Hurd (8) , Rim Hjeij (3) , Sharon D. Dell (9) , Moumita Chaki (10) , Gerard W. Dougherty (3) , Mohamed Adan (11) , Philip C. Spear (12) , Julian Esteve-Rudd (13) , Niki T. Loges (3) , Margaret Rosenfeld (14) , Katrina Diaz (10) , Heike Olbrich (3) , Whitney E. Wolf (1) , Eamonn Sheridan (15) , Trevor F.C. Batten (7) , Jan Halbritter (2) , Jonathan D. Porath (2) , Stefan Kohl (2) , Svjetlana Lovric (2) , Daw-Yang Hwang (2) , Jessica E. Pittman (1) , Kimberlie A. Burns (1) , Thomas W. Ferkol (16) , Scott D. Sagel (17) , Kenneth N. Olivier (18) , Lucy C. Morgan (19) , Claudius Werner (3) , Johanna Raidt (3) , Petra Pennekamp (3) , Zhaoxia Sun (20) , Weibin Zhou (10) , Rannar Airik (2) , Sivakumar Natarajan (10) , Susan J. Allen (10) , Israel Amirav (21) , Dagmar Wieczorek (22) , Kerstin Landwehr (23) , Kim Nielsen (24) , Nicolaus Schwerk (25) , Jadranka Sertic (26) , Gabriele Köhler (3) , Joseph Washburn (10) , Shawn Levy (27) , Shuling Fan (10) , Cordula Koerner-Rettberg (28) , Serge Amselem (29) , David S. Williams (30) , Brian J. Mitchell (12) , Iain A. Drummond (11) , Edgar A. Otto (10) , Heymut Omran (3) , Michael R. Knowles (1) , Friedhelm Hildebrandt (31, 2, 32)

1 UNC - University of North Carolina [Chapel Hill]
2 Boston Children's Hospital
3 UKM - University Hospital Münster - Universitaetsklinikum Muenster [Germany]
4 PUMS - Poznan University of Medical Sciences [Poland]
5 IIMCB - International Institute of Molecular and Cell Biology [Warsaw]
6 Kuwait University
7 University of Leeds
8 Edin. - University of Edinburgh
9 SickKids - The Hospital for sick children [Toronto]
10 University of Michigan [Ann Arbor]
11 Massachusetts General Hospital [Boston, MA, USA]
12 Northwestern University [Chicago, Ill. USA]
13 UCLA - University of California [Los Angeles]
14 University of Washington [Seattle]
15 St James's University Hospital
16 Washington University School of Medicine in St. Louis
17 University of Colorado Anschutz [Aurora]
18 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
19 CRGH - Concord Repatriation General Hospital [Sydney, Australia]
20 Yale University [New Haven]
21 Bar-Ilan University [Israël]
22 Uniklinik Essen - Universitätsklinikum Essen [Universität Duisburg-Essen]
23 UKJEKB - Universitätsklinik für Kinder- und Jugendmedizin, Evangelisches Klinikum Bethel [Bielefeld, Germany]
24 Copenhagen University Hospital
25 MHH - Medizinische Hochschule Hannover = Hannover Medical School
26 University of Zagreb
27 HudsonAlpha Institute for Biotechnology [Huntsville, AL]
28 St. Josef Hospital [Bochum, Germany]
29 Physiopathologie des maladies génétiques d'expression pédiatrique
30 JSEI - Jules Stein Eye Institute [Los Angeles, CA, USA]
31 HMS - Harvard Medical School [Boston]
32 HHMI - Howard Hughes Medical Institute [Chevy Chase]

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.

Domaines: Pneumologie et système respiratoire; Sciences du Vivant [q-bio]; Génétique

Maimoona A. Zariwala, Heon Yung Gee, Małgorzata Kurkowiak, Dalal A. Al-Mutairi, Margaret W. Leigh, et al.. ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6. American Journal of Human Genetics, 2013, 93 (2), pp.336-345. ⟨10.1016/j.ajhg.2013.06.007⟩. ⟨inserm-03887971⟩